UNITED ST AT ES ENVIRONMENTA L PROTECTION AGENCY WA SHINGTON, D.C. 20 460

OFFICE OF T H E ADMINIST R A TOR SCIENCE ADVI SOR Y B O ARD August 8, 2008

EPA-CASAC-08-017

The Honorable Stephen L. Johnson Adm i nistra tor U.S. Environm ental Protection Agency 1200 Pennsylvania Avenue, NW Washington, DC 20460

Subject: Clean Air Scientific Advisory Comm ittee’s (CASAC) Peer Review of EPA’s Integ r ated Sc ienc e Assessmen t ( I SA) for Sulfur Oxid es – Health Criteria (Second External Review Draft, May 2008)

Dear Adm i nistrator Johnson:

The Clean Air Scientific Advisory Comm ittee (C ASAC), augm ented by subjectm a tter-exper t s to f o rm the CASAC Sulf ur Oxides Prim ary NAAQS Review Panel conducted its review of EPA’s Integrated Science Assessmen t ( I SA) for Sulfur Oxid es – Health Crite r ia (Second External Review Draft, May 2008) on July 30-31, 2008. The first draft ISA was reviewed by CASAC in December of 2007 and s ubsequently revised in respons e to CASAC a dvice trans m itted in January 2008. This letter p r esents CASAC’s advice on the second draf t ISA issued in May 2008.

The CASAC finds that the second draft ISA is greatly improved and that the Agency has been responsive to the C A SAC' s earlier review. There are so m e rem a ining concerns as described in our answers to the Agency' s charge questions in the m a in body of

this le tte r. Our m a jor concern is th e conc lus i on s in the ISA regard ing the weight of the evidence for health effects for short-term exposure to low levels of SO 2 . Although the ISA presents evidence from both clin ical and epid em iological studies that indicate health effects occur at 0.2 ppm or lower, the final chapter em phasizes health effects at 0.4 ppm and above. As discussed in our responses to Charge Questions 3 and 5, CASAC believes the clinical and epidem iol ogical evidence warran ts stronger conclusions in the ISA regarding the available evidence of health effects at 0.2 ppm or lower concentrations of SO 2 . The selection of a lower bound concentratio n for health effects is very im portant because the ISA sets the stage for EPA’s risk assessm ent decis i ons. In its draft Risk and Exposure Assessment (REA) to Support the Review of the SO 2 Primary National Ambient Air Quality Standards (July 2008), E P A chose a range of 0.4 ppm – 0.6 ppm SO 2 concentratio ns f o r its be nchm ark analysis. As C A SAC will emphasize in a f o rthcoming letter on the REA, we re commend that a lowe r bound be set at leas t as low as 0.2 ppm.W ith this and other m odifications as reco mm ende d below, CASAC finds the scientific quality of the ISA acceptable for ru lem a king.

CASAC’s response to E P A’s charge ques tions are summ arized below. Individual

recomm endations from Panel m e m b ers to strengthen the final ISA are appended in Enclosure B

. Charge Question 1: T h e framew ork fo r causal determination and judging the overall w e ight of evidence is presented in Chapter 1. Is this the appropriate approach? Is it approp riately applied in the case of SOx? How could the framew ork or its application be refined?

Chapter 1 has been improved, particularly by drawing on recent reports that offer models of approaches f o r causal inf e rence a nd classification schem e s for the weight of evidence for inferring causation. The ISA u tilizes a five-level hierarchy f o r causal determ ination to be consistent with the Guidelin es for Carcino g en Risk Ass e ssment (EP A

, 2005). W e concur with using the five levels but recomm end that the descriptions be changed to b e tte r ref l e c t the leve l of certa inty o rc onf idence in the classif i c a tion of the level of evidence. The phrasing of the sec ond level is particularly problem a tic in its addition of the wording “likely causal re lationship.” The approach to evidence interpretation should avoid using statistic al significance as a criterion for evidence interpretation. CASAC recomm ends that EPA reconsider the language used to describe the weight o f evidence, particula r ly f o r the f i rst three ca tegor ies wh ich cover a range of certainty o rconfidence in causal inference th at extends from full certainty to lesser degrees. The language used should be consistent with other such schem e s used by EPA.

For the cr ite r ia po llutants, the ISA n eeds to a c kn owledge tha t the po lluta nts exis t in comp lex m i xtures and to broadly consid er the implications f o r interp reting the evidence in the ISA. W e al so specifically recom m e nd i m pr ovem ent in the presen tatio n of the epidem iological concepts of e ffect m odifi cation and confounding that are particula r ly challenging in the face o f m u lti- pollu tant m i xture s . Other asp e cts of the chapter also need greater developm ent in cluding the treatm e nt of uncertainty. The concept of “m argin of sa fety” also needs elab oration. Figure 1 is not effective and unless the text is expanded to explain m a ny of th e relationships depicted, it needs to be abandoned o r replaced.

Finally, we applaud the speci fication of questions at the beginning of the first chapte r tha t outlin e spec if ically the in tent of the I S A, and the integ r ation o f the answer s to these questions, as obtained from the evid ence in the ISA, in the con c luding chapter. This stru ctu r e will p r ovid e a cle a r sc ientif ic f oun dation f o r th e developm ent of the Ris k and Exposure Assessm e n t docum ent.

Charge Question 2: Have these revisions to C h apter 2 improved its assessment of the currently available scientif ic know l edge on atmospheri c sciences and exposure and its relevance to the evaluation of hum an health effec t s presented in later chapters?

iiChapter 2 is significantly improved fr om its earlier version and previous comments from the Panel have been taken into account. There are, however, som e points that need to be addressed in greater detail and other points require som e clarification. Since the R E A will f o cus on 5-m i nute ave r ages of SO 2 concentrations, a m o re

comp rehensive discussion of the available 5-m i nute SO 2 concentration data is warranted. For exam ple, a table pres enting inform ation sim i lar to that in Table 2-4 w ould be useful. A better discussion of the discussion of the distributions and tim e -trends of 5-m i nute average con centration s is needed as is great er consideration of which distribution best represents ambient data (norm a l or log-norm a l). Further, the analyses should address correlation between the 5-m i nute and one-hour average concentration distributions. Figure 2-11 needs to be redrafted to pr ovide a better depiction of diurnal S O 2 am bient concentratio ns. The fact that the tren d in SO 2 concentrations is due to changes in SO 2
em issions rather than to changes in m eas ure m ent technique should be stated m o re def i nitiv ely.

The rationale behind the selection of the si x states selected for analysis should be better described; som e consideration m a y need to be given to areas where the potential effect of ship em issions on SO 2 could be significant (i.e., m a jor U.S. ports). Analyses (e.g. stratification for source proxim ity and stre ngth and use of m a ps) of s e lected urban areas shou ld be presen ted to characterize th e representativen ess of am bient m onitors f o r characterizing population exposure. Since AERM OD is used in the RE A, there is a need to describe it in the Annex.

Adsorption of SO 2 onto particles which is discussed in m o re detail in Chapter 3 needs to be f u rther d i scu ssed in Chap ter 2. However, th is will need to be p l aced in perspective because con centration s of particu l ate m a tter (P M) and SO 2 used in th e a n im al toxicological studies discussed in Section 3.1.5 were several orders of magnitude above typical am bient concentrations . In addition, it should also be noted that atmospheric chem istry studies do not indicate signifi cant am ounts of sulfite on atm o spheric PM

Chapter 2 correctly points out the diffi culties asso ciated with characterizin g exposure (e.g., lim ited infor m ation on indoor co ncentrations, and vert ical and horizontal SO 2 concentration gradients). However, the im plications for the characterization of health effects could be better described and discussion on the implied uncertainties expanded. More discussion of th e effect of exercise on health effects in exposure studies is warranted. In particular, th e ISA points out that whether S O 2 is inhaled via nasal vs. oral breathing m a kes a difference for SO 2 uptake, however, th e im plicatio ns for the analys is of the health effects s t udies n eed to be discussed in greater detail.

Charge Question 3: In the revisio n, w e reduced redundancy, added summary sections an d reorganized Chapter 3. In addition, discussions on potential confounding by, and interactions w i th, co-pollutants have been added. The 2nd draft ISA also includes additional analys es of individual-level data from human clinical studies (Sections 3.1.3. and 4.1.1) th at builds upon the analysis included in the 1994 Supplement to the Second Addendum . The toxicology sections w ere

iiireorganiz ed to focus on studies usin g more relevant concentrations o f SO 2 and sections w ere added to better discu ss mode of action and potential pa rticle-S O 2 interactions . We are requesting CASAC rev iew specifically on these analyses as

w e ll as on the integration of the overall eviden ce from the human clinical, animal toxico logica l, and epidemiolog i cal s t udies.

Chapter 3 is vastly improved from the previous draft of the ISA. The new analyses of hum a n clinical studies are helpful. CASAC believes, however, that m o re

em phasis should be placed on effects seen at concentrations lower than 0.4 ppm

. The Panel is concerned about the potential undere stim ation of the proportion of asthm a tic persons affected by short-term exposure to SO 2 because on ly m ild and m o derate asthm a tic ad ults were rec r uited to pa r tic ipate in th e clin ica l stu d ies. People with m o re severe asthm a or poor control of their sy m p tom s m a y be m o re susceptible and m a y respond m o re adversely to SO 2 and discussion of this point should be expanded in the chapter. The potential influence of m e dication use on asthm a tic responses to SO 2 should also be discussed. In general, the eviden ce from the anim al toxicolog i cal, contro lled hum a n exposure, and epidem iological studies has been satisfactorily integrated. However, the gap between the greater level of SO 2 used in the clinical studies and the relatively lower am bient concentrations asso ciated with resp ira t ory m o rbidity in the epidem iological studies needs to be clearly acknowledged. The relevance of the higher dose anim al studies also needs to better deve loped. The results of the studies involving
extrem ely high levels of m e tal oxide or carbon-SO 2 m i xtures suggest that SO 2 effects

m a y be potentiated by co-exposure to particles, but the relevance of these results to

am bient exposures is unclear. Section 3.1.5 s hould be greatly condensed to give a m o re focused discussion of the m echanistic im p lications of the m i xture studies without presentation of experim e ntal de tails. W h ile the ne w su mm ary sections are a welcom e addition to the chapter, their quality is uneven. It would be helpful if these sections were written in a style that ap plied the cau sal in f e r e nce approach o u tlin ed in C h apter 1 in a consistent m a nner.

Charge Question 4: T h e section on concen tration-response relationships in Chapter 4 w a s reorgani z ed and revised to include an alysis of individual- lev e l data from t h e human clinical studies and some additional discussion of the difficulties of discerning a threshold in population-level da ta. In addition, revision s w ere made to better characteriz e groups likely to be susceptible or vuln erable to S O x and the potential size of the populat ion at ris k for SOx-rela t ed health effects. Finally, revisions were made to reduce red undancy w i th material presented in Chapter 3. Have the revisions mad e to Chapter 4 impr oved the characteriz a tion of the poten t ial public health impact of SOx exposure?

Revisions to Chapter 4 have improved th e characterization of potential health impacts of SOx exposure, but additional clar ification, evaluation, a nd amplification is needed. The Panel recommends that EPA revi sit the definitions of susceptibility and vulnerability. The definition of susceptibil ity should consider the formof the doseresponse relationship and the m a gnitude of res ponse at a given dose. Greater clarity and specificity is needed in the defi nition of this concep t if it is to be us ed without am biguity.

ivThe curren t def i nition is lim ited in co ncept and inconsistent w ith toxicological and epidem iological usage. EPA should harm oni ze the definitions of susceptibility and vulnerability across docum ents for intra- Agency and inter-pollutant consistency.

Additional analyses of the cited clinical cham ber data could be perform e d to gain insights regarding the populati on distribution of effects at exposures lower than 0.4 ppm SO 2 ; there appears to be an indi cation of effects below this le vel when the pooled data are considered. Specific details are p r ov ided in individual comments. See comments from Drs. Avol, Hattis, Kinn ey, Pinkerto n, Sa m e t and Sheppard In addition, the dis c ussion should do a better job of acknowledging that epidem iology studies generally lack power to distinguish between linear and non-linear response form s.

A m o re complete d i scus s i on of potentially at-risk (i.e. susceptible and/or vulnerable) sub-populations is needed. The discussion should em phasize the importance of linking populations at potentia l risk due to age and disease status with considerations related to exposure and activity distributions in these groups. The joint distribution of all these factors defines the population at ri sk of adverse health impacts from SO 2 exposures. In addition, discussion of the geographical location of at-risk populations with respect to pollution sources needs to be included a nd related environm enta l justice concerns addressed, if appropriate. EPA needs to provid e a ddition a l ju s tif ica tion f o r

its de cis i on to focus on children and older adults with respect to short term respiratory health effects of SO 2
. Charge Question 5: R e visions w ere ma de to better integ r ate findings from atmospheric sciences, a m bient air data an alyses, exposure assessmen t , dosimetry, and health evidence in Chapter 5. To w h at extent do these findings support conclusions regarding causality o f SOx rela t ed health effects at relevant exposures?

The Panel concurs with the conclusion that short term exposures to SOx are causally related to changes in respiratory responses, however we do not accept the levels on which the ISA focuses. The clinical a nd epidem iological studi es warrant a stronger conclusion about health effects at lower leve ls. The range of exposures emphasized in the ISA (0.4 - 0.6 ppm ) has clearly carried ove r to the thinking used in the REA. Adoption of this range might leave substantia l nu mbers of exercis i ng m ild asthm a tics at considerable risk. Table 5-1 of the IS A presen ts studies showing that 5 – 20% of m ild to moderate as thm a tics exp e rien ce m o derate or greater decrem ents in lung function at S O 2 concentrations as low as 0.2 – 0.3 ppm. For ethical reasons severe asthm a tics were not part of these clinical studies, but it is not unreasonable to presum e that they would have responded to even a greater degree. In addition, the epidem i o logical evidence shows

em ergency room visits and hospitalizations fo r respiratory illnesses associated with 2 4

- hour SO 2 levels below the current standard (0.14 ppm averaged over at 24-hour period). Collectively, this evidence shoul d lead to a conclusion that 0. 2 ppm or even a lower level of short-term exposure is an appropri ate lower bound value for EPA’s benchm ark analysis.

vThe Panel was im pressed by the way the preceding chapters’ inform ation was summarized in a series o f tables th at effectiv ely collated the textual m a terials, tables, and figures from the preceding chapters as well as th e wealth of data con t ain e d in the appendices. The conclusions regarding causality with regard to short-term exposures are reasonable. A better discussion is needed on the range of exposures at which effects are observed in the clinical s t udies and th e m u ch lowe r range at w h ich e ffects are observed in the epidem i o logical studies. In additi on, the importance of identifying susceptible subgroups of subjects, and estim ating the cont ribution of these groups to population shifts in response characteristics m a y be a task for the REA, but that docum ent should be inform ed by a discussion of this issue in the ISA.

The large rq u estion is whether the a ddition a l r e s earch c a rr ie d out in th e last 10 years has led to a substantial change in the s c ien t if ic basi s for m a king decisions regarding the basis for setting stan dards for SO 2 . Although the ISA answers this question affir m atively, the final chapter should be orga nized to answer all of the policy-relevant fra m ing questions introduced in Chapter 1. The answers to th ese questions would greatly im prove the usef ulness of this doc um ent as a scientific prelud e to the Risk and Exposure Assessment

.

W ith respect to the entire ISA, there rem a ins the longstanding issue associated with the Clean Air Act' s single pollutant approa ch to analysis and rulem a king. In the real world, we br eathe com p lex m i xtures of m u ltiple pollutants, thus isola ting the ef f

ects of a single pollutant requires simp lif ying assump tions that depart f r om real world phenom ena. W ith SO 2 in particular, the reality of havi ng to ad just for th e p o ssible confounding contributions of other pollutants m a kes defini tive determ inations of assigned causality a challenge.

In closing, the CASAC is pleased to provide the Agency with advice and

recomm endations in the developm ent of this IS A for Sulfur Oxides, which is a funda m e ntal part of the new NAAQS review process. W e look forward to providing additional advice as the Agency completes the N AAQS review process for sulfur oxides.

S i n c e r e l y , /Signed/

Dr. Rogene Henderson C h a i r Clean Air S c ientif ic Advisory Comm ittee

Enclosures

viEnclosure A



### U.S. Environmental Protection Agency Clean Air Scientific Advi sory Committee ( CASAC) Sulfur Oxides Primary NAAQS Review Panel

CAS AC M E MBERS Dr. Rogene Henderson (Chair) , Scientist Em eritus, Lovelace Respiratory Research Institute, Albuquerque, NM

Dr. Ellis B. Cow ling

, * Em eritus Professor, , Colleges of Natural Resources and Agriculture and Life Sciences, North Carolina S t ate University, Raleigh, NC

Dr. James Crapo ,* Professor of Medicine, Departm e nt of Medicine , National Jewish Medical and Research C e nter, Denver, CO

Dr. Douglas Cra w ford-Bro wn , Professor and Director, De partm e nt of Environm ental Sciences and Engineering, Carolina Envir onm e n tal Program, University of North Carolina at Chapel H ill, Chapel Hill, NC

Dr. Donna Kenski , Director of Data Analysis, Lake Michigan Air Directors Consortium

, Des Plaines, IL

Dr. Armiste a d (Ted) Russell , Professor, Departm e nt of Civil and Environm ental Engineering , Georgia In stitu te of Technology, Atlan t a, GA

Dr. Jonathan M. Samet , Professor and Chair of the Departm e nt of Epidem iology, Bloom b erg School of Public Health, Johns Hopkins University, Baltim ore, MD

PANEL M E MBERS Mr. Ed Avol , Professor, Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA

Dr. John R. Balmes , Professor, Departm e nt of Medi cine, Division of Occupational and Environm ental Medicine, University of California, San Francisco, CA

Dr. Terry Gordon , Professor, Environm ental Me dicine, NYU School of Medicine, Tuxedo, NY

Dr. Dale Hattis , Research Professor, Center for Technology, Environm e n t, and Developm ent, George Perkins Marsh Instit ute, Clark University, W o rcester, MA

Dr. Patric k Kinney , Ass o ciate Professor, Departm e nt of Environm ental Health Sciences, Mailm an School of Public Hea lth , Colum b ia University, New York, NY

* Di d not part i c i p at e i n t h e J u l y 30 -3 1, 2 0 0 8 revi e w of t h e s econ d d r aft IS A.

iDr. Steven Kleeberger , Professor, Lab Chief, Labor atory of Respiratory Biology, National Ins titu te of Environm ental Health Scie nces, Nation a l Ins t itutes of Health, Research Triangle Park, NC

Dr. Timothy V. Larson , Professor, Departm e nt of Civ il and Environm ental Engineering, University of W a shington, Seattle, WA

Dr. Kent Pinkerton , Professor, Regents of the Univer sity of California, Center for Health and the Environm ent, Unive r sity of California, Davis, CA

Dr

. E d wa r d P o s t l e t h wa i t , Professor and Chair, Departm e nt of Environmental Health Sciences, School of Public Health, Univers ity of Alabam a at Birm ingha m, Birm ingham, AL

Dr. Richard Schlesinger , Associate Dean, Departm e nt of Biology, Dyson College, Pace University, New York, NY

Dr. Christian Seigneur , Vice President, Atm o spheric & Environm ental Research, Inc., San Ra m on, CA

Dr. Eliz a b eth A. (Lianne) Sheppard , Research Professor, Biostatistics and Environm ental & Occup a tiona l Health Sc iences, Public Health and Community Medicine, University of Washington, Seattle, WA

Dr. Frank Spei z er , Edward Kass Professor of Medici ne, Channing Laboratory, Harvard Medical School, Boston, MA

Dr. George Thurston , Associate P r ofessor, Envir onm ental Medicine, NYU School of Medicine, New York University, Tuxedo, NY

Dr. James Ultman , Professor, Chem ical Engin eering, Bioengineering P r ogram , Pennsylvania State Universi ty, University Park, PA

Dr. Ronald Wyz g a , Technical Executive, Air Quality Health and Risk, Electric Po wer Research In stitu te, Pa lo Alto, CA

SCIENCE ADVISORY BOARD STAFF Dr. Holly S t allw orth , Designated Federal Officer, Scien ce Advisory Board Staff Office, Washington, D.C.

iiEnclosure B

Individual Comments on the Integrated Science Asse ssment f o r Sulfur Oxides – Health Criteria ( Second External Review Dra ft, May 2 008 ) from Clean Air Scientific Advisory Committee (CASAC) Sulfur Oxid e s Prim ary National Ambient Air Quality Standards (NAAQS) Review Panel

Mr. Ed Avol

....................................................................................................................... 2 Dr. John Balmes

................................................................................................................ 5 Dr. Doug Crawford-Br o wn

.............................................................................................. 9 Dr. Terry Gordon

............................................................................................................ 13 Dr. Dale Hattis

................................................................................................................. 15 Dr. Donna Kenski

............................................................................................................ 18 Dr. Patric k Kinney

.......................................................................................................... 21 Dr. Steven Kleeberger

.................................................................................................... 24 Dr. Timothy Larson

........................................................................................................ 26 Dr. Kent Pinkerton

......................................................................................................... 32 Dr. Edw a rd M. Postlethw a it

.......................................................................................... 35 Dr. Jonathan M. Samet

.................................................................................................. 37 Dr. Richard Schlesinger

................................................................................................. 40 Dr. Christian Seigneur

.................................................................................................... 42 Dr. Lianne Sheppard

...................................................................................................... 47 Dr. George Thurston

...................................................................................................... 48 Dr. James Ultman

........................................................................................................... 51 Dr. Ronald E. Wyz g a

...................................................................................................... 53Mr. Ed Avol

Comm ents on SOx ISA 2 nd Draft

Question 1 (a m odified Chapter 1 on the fram e w ork for causal determ ination) The continu i ng EPA-and-Clean-Air-Act self-im posed restriction to consider individual pollutant effects (in th is case, SO 2 fr om particulate SOx) m a kes the fram ework for evaluation of the overall weight of evid ence a challeng ing one , due to the common sources of pollutant generation (and virtually no difference in the poten tia l ta rgets of

source em ission reductions). The reality of having to adjust for the possible confounding contributions of other pollutants m a kes defini tive determ inations of assigned causality a

m e ssier proposition, sin ce the likely presence of other am bient co-po llutants provid e s a “sm oke-screen” of sorts for the true stim ulator (or stim ulator s ) of response and effect.

The fram e w ork described in Chapter One, aside from the recurring general concern for an archaic approach that attem p ts to evaluate h ealth effects on a discrete pollutant-bypollutant basis in the face of ever-growi ng inform ation about additive and synergistic physical, chem ical, and physiological interac tions, seem s a reasonable way to proceed.

Question 2 (an expanded Chapter 2 on atm o spheric chem istry of SO 2 ) The additional sections about m onitoring info rm ation are usef ul in developing an overall appreciation for the historical m onitoring network and nationally downward trend in SO 2 exposure. My personal opinion regarding the inclusion of design criteria for station placem ent is that there is m o re detail than necessary presen ted here, and m o st of it is generic (to any acceptable m on itoring site’s placem ent).

The im proved inform ation presented does im prove the overall assessm ent of the currently available knowledge and is relevant to subse quent discussions of hu m a n health effects.

Question 3 (a revised Chapter 3 on Integrated Health Effects) The chapter is still a long comp endi um of infor m ation (over 100 pages), but the summary figures are very helpful in providing a “m et a-view” of num e r ous studies. So m u ch inform ation on such a range of health outcom e s is presented that, at chapter’s end, som e sort of distillation of what the chapter conclu sions were would have been helpful. This

m i ght be in the for m of a table, listin g category (morbidit y, mortality, etc), SO 2 exposure (long-term or short-term ), health outc om e (lung function, symptom s , ED visits, hospitalizations, etc), and judgm ent (causal, insufficient, etc), which would assist the reader in interpreting the weight of evid ence from the 100+ pages of data...which is precisely what appears as Table 5.3 in Chap ter 5! Accordingly, it m i ght be worth referring the reader to or providing som e linkage to the Chapter 5 summ ary discussion.

Question 4 (Revisions to Chapte r Four, Public H ealth Impacts) This revised description of th e public health impa cts of SO 2 exposure is substantively im proved, but could still profit from further clarification, focus, and specif i city. The over-arching questions to be addressed include the following: (1) what insights do current data provide regarding the shape of th e concentration-response function for SO 2 ? (2 ) Is

2there evidence of a threshold of response? (3) Are there popula tions at risk? (4) If there are populations at risk, who are they? To th e credit of the ISA staff, these issues are discussed, but they are not always clearly/succi nctly summ arized or brought to som e final resting point in the docum ent.

For example, the presentation of concentr ation-response functions and the topic of thresholds of response are understandably li nked, but the presentation in the docum ent is inter-twined (in sections 4.1.1 to 4.1.3) and thus more difficult to follow than need be. W ith regard to the question of concentrati on-response functions, the presented data from clinical and epidem iological studies suggest there is support for a linear concentration– response function claim (more supportive from the clinical cham ber studies, less convincing but som e what supportive from the epi studies). W ith regard to a threshold of response, the data are inconclusive. This discussion, particularly in Section 4.1.3, should be separated into two sections (one on the concentration-response function, and the other on threshold response).

The discussion of susceptible and vulnerable pop ulations (Section 4.2) is also in n eed of

som e im proved specif i c i ty (but is ad m ittedl y improved over the prev ious version ) . Much of the appropriate inform ation is contained in the discussions, but structurally, the
respec tive s ection s do n o t always f o llow the specified title or deliver on the prom ised topic. There rem a ins som e confusion about definitions of “s usceptibility ” and “vulner a bility”. Reasona ble working def i nition s a r e provid e d in the tex t (a t the bottom of p4-9 and top of p4-10), but then these are lum p ed together into a discussion of “som ewhat sensitive subgroups” a few lines later (lines 8-14, p4-10).

A discussion about the potenti al importance of genetic fact ors is presented in Section 4.2.2, but much of the two-page discussion is generically about air pollution and not specifically about SO 2
.
Section 4.3 (which needs to be re-titled to “Populations at Adverse Risk” or som e thing, since the current title is the chapte r title ) is a v a lu able pe rspective on how to think about the m u ltiple health ou tco m es being presented.

Section 4.3.2 (Estim ation of Potential Num b ers of Persons in At-Risk Susceptible Population Groups in the US) doe sn’t quite deliver on its title prom ise, in that num bers are estim ated for only a few of the s e veral su sceptible sub-groups identified. Still, the point is m a de that m a ny people are potential at increased risk for exposure and possible response. T h e concluding paragraph in th e chapter (lines 10 through 18 on p4-23) provides a d eclarative o v erview on the issue (in essence, that there are co uld be a considerable public health impact, because th ere are large nu mbers of susceptib le sub

groups), but seem s to fall short by not saying something about the likelihood of exposure to leve ls like ly to trigge r the rang e of health outcom es identified.

(One final note – is the comm ent regardi ng Figure 4.6 “...demonstr ating that the SO2- related excess risk for asthm a is, on averag e, 50% higher am ong children when comp ared

3to risk estimates that include all ages...” (lines 7-9, p4-23) ov er-reach ing, given the error bars, available data, and risk range [~RR 1.05-1.1]? )

Question 5 (revised Chapter 5 on In tegrated Findings of Causality) This chapter has a sign if icant task an d a larg e bo dy of m u ltiple outcom e data f r om over 20 years to summ arize. The summary Table 5.3 is especially usef ul, in distilling the current judgm e nts to brief paragraphs of conclusions for endpoints of potential health inte rest.

The docum e n t provides an interesting seri es of comm ents regarding “previous conclusions” and “current conclusions” in Tabl e 5.3, but it is not clear to what “previous” review these comments refer. (Presum a bly, these “previous” comments refer to the 1996 NAAQS S O 2 review, but one could also interpret this as a refe rence to an e a rlier ve rsio n of the ISA). This should be explic itly specified in the document.

The larger question here is the following: ha ve the additional years of data, research, and observations changed our judgm ent re garding the health effects of SO 2 ? The comments in Table 5.3 regarding previous and current c onclusions m a ke it difficult to determ ine, and should be simp lified to reflect a cl earer conclusion of where we are today.

4Dr. John Balmes

Comm ents on SOx ISA -- 2 nd Draft

Charge Question 3: In th e revision, we reduced redundanc y, added summ ary sections and reorganized Chapter 3. In addition, discussions on potential confounding by and interactions with copolluta nts have been added. The 2nd draft ISA also includes additional analyses of individual-level data from hum a n clinical studies (Sections 3.1.3. and 4.1.1) that builds upon the analysis incl uded in the 1994 Supplem ent to the Second Addendum

. The toxicology sect ions were reorganized to focus on studies using m o re relev a nt con centr ation s of SO 2 and sections were added to better discuss m ode of action and potential particle-S O2 in teractions. W e are requesti ng CASAC review specif ic ally on these an alyses as well as on the integr ation of the overall evidence from the hum a n clin ical, anim al toxicolo gical, and ep idem iol ogical studies. T o what extent is the discussion and integration of evidence from the anim al toxicology and controlled hum a n exposure studies and epidem iologic studies technically sound, appropriately balanced, and clearly comm unicated?

GENE RAL COMMENT S

The revised Chapter 3 is much improved by virtue of the reduced redundancy, added summary sections, reorganiza tion, and additional discussions involving co-pollutants. The new analyses of human clinical studies in Sections 3.1.3 and 4.1.1 are helpful. In general, the discussion of the results of th e anim a l toxicological, controlled hum a n exposure, and epidem iological studies that ha ve been reviewed is technically sound. T h e

m a jor exception to this comm ent is the discus sion of the effe ct of SO2 on lung function responses to inhaled house dus t m ite allergen in asthm a tic adults with pre-existing sensitization to this allergen on page 3-31. As written, the draft indicates that SO2 “enhanced sensitization to house dust m ite”. This is incorrect. In fact, it would be unethical to induce or enhan ce sens itization to a common aer oallergen in hum a n subjects.

The integration of the anim al toxico logical, controlled hum an exposure, and epidem iological studies that have been revi ewed is also technically sound, balanced, and clearly com m unicated with several exceptions on page 3-91. The summary statem ents about the evidence in Sec tions 3.4.2.2 and 3.4.2.3 are too strong as worded. I have suggested revised wording (see below in Specific Comm ents).

Perhaps m y biggest concern about the current draft of Chapte r 3 involves the references. Many papers cited in the text are simply not liste d in the Ref e rence s , and som e citatio ns are obviously wrong (see som e exampl es below in Specific Comm ents).

SPECIFIC COMMENT S

p. 3-13, line 28 The word “allerg ic” should be deleted from this sentence. SO 2 is
too sm all of a m o lecule to elic it an alle rgic response on its own. The presence of

5eosinophils in bronchoalveolar lavage fluid doe s not m ean that SO2 induced an allergic response. In addition, the G ong et al. (2001) study is not listed in the References.

p. 3-30, line 11 The Gong et al. (2001) study is both not listed in the References and is not a sheep study.

p. 3-31, lines 8-14 The two st udies cited in this paragr aph did not show that SO2 “enhanced s e nsitiza tion to the a lle rg en in asthm a tic individuals. ” Rather, these two studies sho w ed enhanced airway responses to inhale d allergen in asth matic individual with preex is ting sens itiz ation to hou se dust m ite

. p. 3-31 , line 7 The word “preexisting” should be deleted from this sentence. Increased morbidity with infection does not necessarily m ean that there w a s preex istin g disease.

p. 3-32, lines 24-25 For clarity, th e sentence should read “...and was also higher in the winter m onths (m ean 25.7 ppb [SD 15.8]) than in the summ er m onths (m e a n 10.6 ppb [SD 15.1].”

p. 3-39, line 11 The Ito et al. (2003) stud y is not listed in the References.

p. 3-39, line 13 This sentence should be re vised as follows: “A study conducted in New York City...” In add ition, this study is not list ed in the R e ferences.

p. 3-42, line 25 For clarity, this sentence should be revised as follows: “In
summary, only a few st udies provide results forrespiratory health outcom es other than asthm a and COPD , and these results are m i xed .”

p. 3-45, lines 14-15 I would de lete “and to a more lim ited extent the hum a n clinical studies” from this sentence.

p. 3-46, lines 24-26 This sentence should be revised as follows: “These findings of incre a sed airway resistance are in concordance wi th the lim ited epidem iological study results of Taggart et al. (1996) that showed SO2-induced increases in AHR a m ong asthm a tic ad ults

. p. 3-46, line 31 I would add “non-elderly” before adults in this sentence.

p. 3-48, line 4 “bronchial respons iveness” should be changed to lung function
responses . A decrease in FEV1 is not n ecessarily a bronchial response.

p. 3-49, lines 1-3 The dog study discu ssed in the 1982 AQCD should be cited.

p. 3-51, lin e 25 and p. 3-52, line 1 For clarity, this statem ent should be s p lit into two
sentenc e as f o llows: “... of sulf ite . D ose-dependent decreases... and above were also observed .”

6p. 3-53, line 8 The Peters et al. (1996) paper cited appears to be the wrong reference for the Hong Kong study.

p. 3-58, line 4 The Routledge et al. (2 006) study cited is not listed in the References

p. 3-59, line 3 The Gold et al. studies cited are not listed in the R e ferences.

p. 3-61, line 4 The Peters et al. (2000) study cited is not listed in the References.

p. 3-61, line 15 The Dockery et al. (2005) study cited is not listed in the References.

p. 3-64, line 1 The Liao et al. (2005) study cited is not listed in the References.

p. 3-67, line 1 The Ballester et al. 2001 study cited is not li sted in the References.

p. 3-75, lin e 4 “...the asso ciation between air po llu tants and m o rtality was

exam ined...”

p. 3-76, line 2 The Le Tertre et al (2002) and Ballester et al. (2002) studies cited are not listed in the References.

p. 3-77, line 26 and p. 3-78, line 1 For clarity, I would revise these two sentences into one as follows: “..health effects studies in Asia that summarized the results from mortality and hospital adm i ssion studies publ ished in the peer-re viewed scientific literature from 1980 through 2003.”

p. 3-91, line 2 I would revise this st atem ent as follows: “...studies do not provide sufficient ev idence to infer that long-term exposure to am bient SO2 has a detr im ental effect on lung function.”

p. 3-91, lines 18-19 Sim ilarly, I would revise this statement as follows: “...studies do
not provid e sufficient ev idence to infer that long-term exposure to am bient SO2 causes prolonged ef fects on lung m o rphology.

p. 3-94, line 11 I would add “am bient” before SO2 in this sentence.

p. 3-97, line 28 “Furtherm o re, the epidem iological studies do not provide...”

p. 3-102, line 19 The Liu et al. (2003) study cited is not listed in the References.

p. 3-102, lines26-27 For clarity, I would revise this sentence as follow s : “The m o st robust association with intrau ter i ne mortality was observed f o r an index of three gaseous pollutants N O 2, SO2, CO).”

7p. 3-105, line 2 The Japanese study disc ussed in the 1986 Secondary Addendum should be cited.

8Dr. Doug Craw ford-Br o wn

Comm ents on SOx ISA – 2 nd Draft

My comm ents here focus largely on Chapte rs 4 and 5, although it was necessary to review th e earlier ch apters as well because Chapter 5 especially draws on m a terials from those earlier chapters. It is clear to m e that the EPA is ge tting bette r at th is process of creating an ISA. The docum e nt is well orga niz e d ; it is ea sy to f o llow the reasoning u s ed by the autho r s; and they appear to me to have reached the appropriate sum m a ry conclusions on the ability of SOx to produce effects even at levels below the current NAAQS, at least for short-term exposures. Th e docum e nt overall provides an adequate basis “to provide support for future risk, e xposure and policy assessm ents”, in the sense that it establishes the existen ce of effects in policy-relevant ranges of exposure, identifies issues associated with ex posure, and identifi es sensitiv e subp opulations. It would not be possible to use the docum ent alone as the ba sis for perform i ng an actual risk assessm e n t because there is in adequ a te assessm ent of exposures nationally or in specific subpopulations. But I presum e such a for m al, quantitative risk assessm ent would be the task of the E xposure and Risk Assessm e nt docum ent. Still, I conti nue to have trouble understanding the role of the ISAs in m eeting the needs of risk assessm ent. This docum ent continues the pattern of being an inadequate basis for such a quantitative approach, ev en if it does system atically rev i ew th e evidence o n which such a quantitative

assessm ent m i ght ultimately b e bas e d.

My specific comments are:

1. I like the for m ulation of th e questions on page 1-2. They seem to be a refinem e nt of these questions in previous ISA docum ents, r ecognizing the need not to just consider new inform ation but to integrate new in form ation into past assessm e nts.

2. On page 1-5, the authors note that associa tion s are not sufficient for p r o o f of a causal rela tionsh i p. Later they m e ntion that epidem iological studies provide evidence of an association. Still later in the docum ent, they use the epidem iological evidence as a basis for concluding that there is a causal relationship. This is not consistent, although I think the inconsistency begins with the first clai m : that associations do not prove causality sufficiently. This needs som e nuance, as a ssociations ARE an im portant component of causal reaso n ing, even if not fully co mpelling. I disagree with views th at association s are not relevant in claim s of cau sality – they can in f act be com p elling, rational evidence if suf f i ciently well es tablis hed and re liable.

3. In the figure on page 1-6, I note that som e aspects of the bottom half of the figure, such as lifestyle, CAN be influenced by community norm s , and so are not strictly individual-level factors.

4. The topic of m u ltifactorial causation on page 1-9 is in te resting. But th ere are real questions as to whether policy can deal with such comp lex m i xtures , leading perhaps to

9different standards in different regions wher e the m i x differs. The common basis could be overall risk, not the allowed concentration of any one contam inant, bu t th ere will still be signif i can t issues of equitab l e trea tment of the class of em itters in dif f

e re nt reg i ons if the

m i x differs between those regions (which in tu rn would require different levels of control on the sam e class of em itters in dif f

e r e nt reg i ons).

5. On page 2-39, the authors state that e xposure m i sclassification m a y result if total hum a n exposure is not disaggregated. I am not sure WHICH e xposure is then

m i sclassified. Is it the exposure to ambient le vels? If one is using total exposure to S O x, perhaps through personal m onitors, in epidem iological studies, there is no exposure

m i sclassif i c a tion due to a lack of disaggregation. There W O ULD be m i sclass if icatio n if one is trying to get at the effect of a m bien t, policy-relevant expos ures alone. I assum e they don’t mean m i sclassifi cation of total exposure.

6. Table 2-9 presents a num b er of studies, and then the authors appear to settle on 0.13 as the slope. This value is the highest one in th e table by a factor of 2 to 3, and I don’t feel the authors have explained adequately why th ey chose this particular result from a m ongst those in the table. I’m sure there is a rati onale, bu t it do esn’ t c o m e across in the writing and so ther e will be susp icion tha t the choice was based on co nservatism rather than th is being the best study.

7. The discussion of Berkson type errors on page 2-53 is correct , although I don’t see where the au thors even tu ally con c lud e whether th e erro rs in th e specific studies used h e re

are or are no t Berkson ty pe. I presum e they assu m e the error s will lead to

m i sclassification and bias towards the null, but I can’t s ee th is stated clearly. If there IS bias towards the null, they should state th is as a final conclusion, which then has implications for application of any slope fact ors and the degree to which a standard is health protective with a m a rgin of sa fety.

8. On page 2-54, the authors have not noted that the slope factor can be incorrectly increased if location near a source is correla ted with sensitivity. For example, if poverty causes sensitivity due to poor nutrition, and la nd prices decline the cl oser one gets to a

m a jor source, then expo sure and sen s itiv ity are c o rrelated an d beta will b e incr eased above that found when this correlation is not present.

9. In the section on Dosim e try, the author s have summarized the studies adequately. However, there rem a ins the problem of how SO x gets into the deep lung given the rapid absorption in the nasal p a ssages, o rh o w its m ove m e nt into the surface of hygroscopic particles m i ght affect this penetratio n. I cam e away from the chapter not quite clear whether the authors were saying penetration to the deep lung is insignificant, significant only for m o uth breathin g, or unknown quantitatively.

10. On page 2-61, the m i ddle paragraph seem s inconsistent. How can uptake in a 3 year old be slightly higher than for an adult but uptake per unit surface area be the sam e , given the sm aller s u rface area in a 3 year o l d? It seem s to m e a higher uptak e in a 3 year o l d

10would produce an even larger d i fference in uptak e per unit su rface area. Or could the authors be in som e sens e conflati ng uptake fraction and total uptake?

11. The figures in Chapter 3 are good and useful . It is especially good that they are in a consistent form at. The authors could impr ove the text by describing how the studies could be combined quantitativel y or at least qualita tiv ely. Otherwise, th e reade ris lef t with just “eye-balling” the graphs for a m ean value - or choosing a single study - IF quantitative analysis is needed. Is m e ta-ana lysis not appropriate, and if not, why not? B u t perhaps the figures are there only to suggest a robust claim of an a ssociation. Still, the authors shou ld sta t e th at if it is the ca se. Th e read er also n e ed s to be to ld whether th e studies in th e figures rep r esent a full sam p ling of such studies, or ha ve been selected from a larger set to for m a subset – this subset would then need to be defined.

The following questions are related to Charge Question 4:

12. In Chapter 4, I continue to have a probl em with the ISAs separating exposure levels and sensitivity in determ ining the public he alth impact. The aut hors do a good job of describing the sensitive subpopulation, and then of estim ating the size. It is evident that there are a significant nu mber of people who f a ll into th is ca te gory. But ha ving sensitiv e people present does not equate to a public he alth impact unless exposures are sufficient, and this chapter m a kes no attem p t to quantify the exposures to these people. So I am not convinced that tables such as 4-2 provide a quantitative m easure of public health im pa ct.

13. On page 4-1, there is m e ntion of a popul ation-response threshol d. I don’t know what this term m e ans. Populations don’t have thre sholds, individuals do and these thresholds are dis t ributed. There are several places in this c h apter whe r e the au thors m a ke it sou nd as if there are population characteristics such as thresholds that can be found in studies, and I don’t believe there are. The belief in popula tion thresholds also is inconsistent with earlier claims in the chap ter that intersubject variability is one of th e causes of linearity of population response at low exposures.

14. I don’t understand why the exposure-response section is not placed into Chapter 3. Surely this is both important inform a tion fo r that chapter, and is in fact th e MOST important infor m ation for understanding th e effect of any lowering of the NAAQS.

15. It is unf ortunate that the clinical E-R curves do not extend down into the region of policy interest. Figures 4-2 and 4-3 suggest th ere m a y be some leveling of the curves in the lower region of exposure, which has signifi cant im plications fo r the increm ental or

m a rginal ef fectiv eness o f policies th at push expo sures be low these levels.

16. It would be useful to show the exis ting NAAQS level on these E-R curves, so the reader can s ee where ex trapolation is needed. This is particularly important because the units of the X axis change be tween several of the figures.

1117. The complexity of the curve in Figure 4-5 is intriguing, as we find the sam e thing in radiation dose-response curves. It usually occurs when there are comp eting beneficial and detrim ental effects at low exposures, due to compensatory m echanism s kicking in.

18. On pages 4-9 and 4-10, a susceptible s ubpopulation is defined as one that m i ght show effects below concentrations needed in the general populati on. This is m u ch too vague of a statem ent, as it applies to any individual whose indivi dual threshold is below the population m e dian (50% of the population therefore being susceptible). And again, there IS no general population response, only the aggregate re sponse of individuals with a distribution of thresholds. Bette r definitions of susceptible and sensitive are needed, ones rela ted in so m e way to percen tiles of the in tersubject variability distributions and some notion of biom odality o f these dis t ributions.

Based on Comments 12-18, I judge that Chapter 4 is better overall than the previous draft, and is nicely organized for the kinds of inform ation presented. But I continue to have problem s with the way in which public health impact is qua ntified. I don’t believe this chapter provides quantitative inf o rm ation on actual im pacts, but rather the POTENTIAL for impact s if exposures are sufficient.

19. Figure 4-6 suffers from having a wide ra nge of ages in the young group (0-14 years). Is there no way to narrow in on the mu ch younger ages where sensitivity seem s especially pronounced?

The following comments apply to C h arge Question 5:

20. Chapter 5 continues the pattern of havi ng little for m al fram e w ork for integrating inform ation. The EPA seem s to cite a different so urce for fram e w orks in each ISA (h ere it is the NAS Institute o f Medici ne Report). I don’t have an a lte rnative to of f

e r, so just believe it w ould be best if the authors just st ate the principles they are us ing directly and not rely on a particular source (requiring th e reader to go back to those sources for clarification )

. 21. On page 5-2, line 20, a causal relationshi p is inferred (reasonabl y), but needs to be

accomp anied by a statem ent of the levels of exp o sure at which the relationship applies. The existing statem ent is too broad. There ar e causal relationships between exposure and adverse effect for all things in th e w o rld, at some level of exposure.

22. The discussion of uncertainty throughout is inadequate. It could lif ted out of here and placed down into any of NAAQS ISAs, it is so g e neric. There needs to b e a better summary of the uncertainty and its implicati ons for specific judgm e nts that m i ght be required in exposure and risk assessm ents.

Overall, Chapter 5 provides a good comp endium of infor m ation that should prove useful for the expo sure and risk assessm ent stages . It adequately summa rizes causal claim s , although I d on’t believe it prop erly p l aces caveats with resp ect to the exp o sure lev e ls at which these causal claims are strong.

12Dr. Terry Gordon

Comm ents on SOx 2 nd Draft ISA

General Comments:

This is an ex cellent draft ISA and for th e m o st part is clear and logical. The authors have m a de logical connections betw een the epidem iology, clinical, and anim al studies and arrived at fa ir conclusions regarding the advers e h ealth effects associated w ith

am bient exposure to SO 2 . Also, the order of the sections in each Chapter is very good. Perhaps, NCEA should form alize the order and f o rm at of sections so that future ISA’s follow this order (to avoid everyone’s suggestio n to change the order to their individual preferences).

Charge Question 3: “In the revision, we reduced redundanc y, added summ ary sections and reorganized Chapter 3. In addition, discussions on potential confounding by and interactions with copolluta nts have been added. The 2nd draft ISA also includes additional analyses of individual-level data from hum a n clinical studies (Sections 3.1.3. and 4.1.1) that builds upon the analysis incl uded in the 1994 Supplem ent to the Second Addendum

. The toxicology sect ions were reorganized to focus on studies using m o re relev a nt con centr ation s of SO 2 and sections were added to better discuss m ode of action and potential particle-S O2 in teractions. W e are requesti ng CASAC review specif ic ally on these an alyses as well as on the integr ation of the overall evidence from the hum a n clin ical, anim al toxicolo gical, and ep idem iologic a l stud ies.”

The reduction in redundancy and the addi tion of summ ary sections has aided in

m a king this Chapter clear and concise. The auth ors have red u ced the an im al studies so that a true picture (of their contribution to understanding the biologic plausibility of the adverse effects of SO2) is now presented. The addition of the toxi cology section that discusses potential part icle-gas interactions and enhanced responses in exposed anim als is very appropriate in the level of de ta il and its re le vance to the ISA.

Charge Questions 4 & 5 : The rev i sio n s are ex ce llent and m a de the chapters very readable with m i ni m a l overlap with Chapter 3 and each oth e r. The dos e-respon se evaluations are appropriate, but the final conclu sions in Chapter 5 m i ght be wo rded m o re strongly so that the REA working group has m o re guidance as to which health endpoints and data sets (epidem i ology and/or clinical) are appropriate for risk evaluations.

Detailed Comments:

Page 1-1, line 13 – W h ile this statement is probably true for sulfite, given the added section(s) on particle-sulfur dioxide inter actions, it seem s prem ature to conclude on the f i rst page of the ISA tha t sulf uric a c id ( poten tia lly layer e d on p a rticle s) a r e present in insignificant concentrations in the ambient environm ent. Page 1-5, line 11 – typo: data comp lem e nt Page 2-44, line 11 – Chao ref is m i ssing here (2001 ref?).

13Page 2-52, lines 5-16 – T h is section is a bit redundant with sim ilar discussions on page 2- 47 lines 7 & 8, page 2-48 lines 1-5, and page 2-42 lines 19-28. Possibly com b ine in one place? Page 3-6, lines 3 and on – Should a brief disc ussion of sulfuric aci d be added to the discuss i on o f sulf ite che m istry/inte ra ctions /m etabolism ? Page 3-7, lin e 9 – Becaus e line 5 m e nti ons ‘cholin ergic’ pathw a ys, saying that acety l cholin e is ‘ also thought to be invol ved....’ is incorrect. Page 3-12, figure 3-1 – Add ‘provocativ e’ to the definition of PC(SO2). Page 3-14, lines 19-30 (and onto the next page) – This section should be condensed to a couple sen t ences or cu t b ecause of th e que stionab l e relevance of 100-2000 ppm sulfur dioxide even if the dosing was brief or in vitro. Page 3-27, line 8 – Please add refs fo r the ‘several other studies....’. Page 3-31, line 5 – Insert ‘pseudo-‘ befo re ‘m easure of airway obstruction’ Page 3-37, Figures 3-6 & 3-7 – W oul d a m e ta-ana lysis be appropriate for these studies? Also, The visual separation of the ED visits and the Adm i ssions studies should be m o re distin ctly la beled. Page 3-39, line 13 – ‘study conducted in ?? ’ W h ere? Page 3-40, line 13 – A positiv e asso ciation fo r th e Lee, 2002 study is no t presented in Figure 3-7. The only Lee study in the figure has a negative association (2006). Typos? Page 3-50, line 15 – Chen, 1992? Page 3-55, line 22 – Is this statem ent true rega rding adults? Page 3- 25 says inconclusive evidence. S hould the text read ‘older adults’? Page 3-57, line 1 – Should the word ‘peak ’ be inserted before ‘am b ient’? Page 3-57, line 18 – W h at are ‘c onsequent cardiac deaths’? Page 3-83, line 13 – ‘and/or’ is unclear Page 3-85, lines 4-10 - μ g /m 3 should be converted to ppm for ease of reading. Page 3-92, line 10 – This statem ent about 3 other recen t stud ies should be deleted or expanded/referenced. Page 3-99 – This section is nicely written and clearly hits the right level of discussion of high dose studies and their quasi-relevance. Page 4-3, figure 4-1 – Inclusion of 0.10 a nd 0.50 in the bar graph im plies that zero percentage changes occurred vs. the actua l absence of data at those exposure concentratio ns. Page 4-6, line 8 – This sentence is not cons istent with figure 4-5 which shows no real change at 10 ppb. Page 5-2, line 1 – Is this sent ence accurate? ‘west to eas t’ im plies a grad ient from the west coast to the eas t co ast. Page 5-10, 5-11 – A nicely written evaluation. Page R-24 – Zeger ref has a typo on the pages.

14Dr. Dale Hattis

Comm ents on SOx ISA – 2 nd Draft

Response to question 4 and to som e extent que stion 3 on the analysis of individual-level clinical concentratio n-response data f o r the short te rm bronchoconstriction response to SO2

. I was encouraged that the ISA authors include d empirical inform ation from three papers by Linn et al. (1987, 1988, and 1990) that are sim ilar to the Horstm an et al. individual data for these responses that I analyzed in m y comm ents to the earlier draft of the ISA. Unfortunately there does not seem to have been any effort to comp are the risk as sess m e nt implications of the Linn et al. data with thos e of the Horstm a n data, let alone put them in
to a com b ined analys is for deriv a tio n of an overall e s tim ate of the concentration-response function for asthm a tics. The concentration-resp o n se section of the REA also lists sev e ral other sources of individual data on sim ilar responses that have not been summarized or analyzed as of yet.

Three types of infor m ation can readily be ex tracted from the existing body of clinical observations: The ED50 for particular re sponses, the breadth of the population distriubiton of thresholds, and the form of the distribution (i.e. does it appear to be lognorm a l, or som e m o re com p lex shape? )

For reference, the Horstm an et al. paper gave individual SO2 threshol d co ncentr ation s f o r 27 asthm a tics for a doubling of specific airway resistance. These data are reasonably, but not perfectly comp atible with a lognorm al distribution (Figur e 1). (In this figure, the straight line repres ents a fitted logno rm al dist ribution for the d a ta. The s l ight departures of the data above the line on both the low and higher-concentr ation ends of the distribution m a y suggest som e tendency towa rd bim odality in the underlying distribu tion of individual thresholds, but these data are not sufficient to make a firm conclusion on that po int). By averagin g the logarithm s of the individual th resholds for this effect w e find an ED50 (geom e tric m ean dose expect ed to produce the response in 50% of an exposed asthm a tic concentration) of 1,040 ppb, with 90% confidence lim its of 739-1475 ppb. From t h e standard deviation of the loga rithm s of the individual values we find a
geom etric standard deviation for interindiv idual variability in the thresholds of 2.38—

m eaning that based on these data, 90% of the ind i vidua l thr e s holds in a s i m ilar population of asthm a tics should be exp ected to be between 250 and 4340 ppb.

The newly presented inf o rm ation from the Li nn et al papers f o r the sam e response are unfortunately not given as i ndividual values, but essentia lly in histogram for m —the

num b er of asthm a tics studied who respond at a f e w discreet dose levels. I have analyzed these assum i ng a lognorm a l distribution of indi vidual thresholds using an Excel program adapted from Haas (1994) and used ex tensively in m y prior work on hum an interindividual variability in susceptibility (Hattis et al. 2001). The data provided from the Linn et al. papers suggest an ED50 for th e doubling of specific airway resistance in exercising asthm a tics of about 580 ppb—a li ttle lower, but probably not significantly lower than the range ind i cated by the Horstm an e t al. data. (I did not assess the

15confidence lim its for the ED50 in this case) Th e Linn et al. data also ind i cate a sligh t ly greater am ount of interindivi dual variability than those of Horstm an—a geom etric standard deviation of 2.85 with 90% confid ence lim its of 2.10-5.75. Together, if we

assum e a lognorm a l distribution of individual th resholds as before, th e central estimate of interindividual variability and the central esti m a te of the ED50 from the Linn et al data would indicate that 95% of exercising asth m a tics should have this response at between 104 and 3250 ppb. Unfortunately, there is reason to doubt that the distribution is perfectly lognorm a l—a goodness of fit test i ndicates a barely stat istically significant departure of the data from expectati ons from a lognorm a l model at P < .05.

There are a couple of ways to com b ine these da ta for an aggregate analysis. One simple way that I d i d was to add the Horstm an observations where they would fall in the histogram -like data from the Linn et al. pape rs. When this is done, the E D 50 indicated by the com b ined data is just under 700 ppb and the geom etric standard deviation for interindividual variability is 2.52 with 90% confidence lim its of 2.01-3.83. The revised central estim a te ED50, com b ined with the central estim ate of the geom et ric standard deviation would indicate that 90% of exer cising asthm a tics should respond between 150 and 320 ppb. Again, however, the com b ined da ta depart from expectations of a lognorm a l distribution model at a P level of sl ightly less than 0.02. In further exploration of the com b i n ed data (including experi m e nts of other research groups) I would

recomm end an attemp t to fit a m i xture of two lognorm a l distributions. I could not
attem p t this in this analy s is, however b ecause a m i xture of two lognormals invo lves estim ation of 5 param e ters (two m eans, tw o standard deviations and a param e ter to

m easure the fraction of the populatio n that be lon g s to each com ponent distribu tion ) and the Linn et al. data are aggregated only into 4 rang es. There is likel y to be an infinite

num b er of perfect-fit solutions when one uses only 4 data points to estim ate 5 param e ters.

If

it is of in terest to EPA staf f

, I will provide the Excel spr e a d sheet show ing thes e calcu lations.

References

Haas, C. N. "Dose Response Analysis Usi ng Spreadsheets" Risk Analysis 14:1097-1100 (1994).

Hattis, D., Russ, A., Goble, R., Banati, P., and Chu, M. “Human Interind ividual Variability in Susceptib ility to Airbo r ne Partic les

, ” Risk Analysis , Vol. 21(4), pp. 585- 599 (2001).

16Figure 1

2 1 0 -1 -2 -1 0 1 2 

## Lognormal Plot of the Distribution of Individual Sensititivities (SO2 Concentrations Needed to Double Specific Airway Resistance) For 27 Exercising Asthmatics (Horstman et al. 1986)

Z-ScoreLog(ppm SO2) y = 0.0189 + 0.374x R^2 = 0.934

17Dr. Donna Kenski

Comm ents on SOx ISA – 2nd Draft

General comments: The revisions to Chap ter 2 have improved it substantially. In particular, S ections 2.5.3 and 2.5.4 on exposur e m easure m ent errors were im proved and clarified. The added tables and discussion we re helpful. The added inform ation on 5-

m i nute averages was a good star t, but lacked enough detail to for m adequate basis for decision-m a king. The dism issal of these data because of the voluntary nature of the reporting an d their variability over tim e and sp ace is troublin g. In ligh t o f the num ber of health studies showing effects at 5- to 15- m i nute exposure times, the importance of the inform ation for the Risk and Exposure Asse ssm e n t, and given EPA’s request that the states collect this data, it seem s unreasonable to dism iss it in this docum ent without even a rudim e ntary summary of the data. The RE A goes on to glean im portant inform ation from the relationship of the 5-m i nute peaks to hourly m eans, so the very lim ited discussion in this docum ent is surprising. Th is particular shortcom ing was not apparent in the previous version of the ISA, before the REA had been drafted. The rem oval of the NOx infor m ation from Annex B wa s a good deci sion; it m a kes it m u ch easier to find the relevant data for SO2. Som e specific comm ents follow:

2-1 line 13 The initial p h rase, “ I ndustrial em issions...” is som e what

m i scharacterized; p e rhap s the au thors m eant anthropogenic em issions? Utility em issions are usually regarded separate ly from industrial em issions.

2-2 1 st paragraph. This section still needs a sim p le sentence quantifying biogenic or natural sources. It is un acceptable to spend 2 paragraphs d e s c rib i ng natu ral sources and still not quantify them except as ‘small’, which could be 10% or 1% or 0.01%. E v en Table B

- 3 doesn’t do so; th e reader is left to infer that such

em issions are less than 0.00 Tg/yr.

2.2. Line 12 Refers to Table B-6, which doe s not exist. It doe sn’t look like this data is available in the revised Annex.

2.3 line 14 Reference to Annex B.5 should be B.6

2.8 Sec. 2.4.1 The addition of the m oni tor siting criteria was helpful. The openpath information is probably unnecessar y, however. The sampling and analysis discussion didn’t describe any open path instrum e nts for SO2 and since these are a tiny fraction of the reporting network, if there are an y at all, it could be deleted without harm to the rest of the discussion.

2.11 The new figures 2.1-2.6 are a useful addition. However, the rationale for choosing th ese 6 areas for focus need s to be clearly stated. Was it b ecause they have the
most m onitors, or the highest concentrati ons, or the m o st spatial heterogeneity or hom ogeneity?

182-11 line 16 ...as well as the subset of monitors in Cuyahoga County.

2-19 line 9 ‘Overrepresentation’ sounds j udgmental. ‘Predom i nance’ m i ght be a better word choice

2-23 Fig. 2-11 At the risk of sounding like a broken record, I wi ll point out again that this figure is a poor depict ion of diurnal cycles. If the po int is to show diel variation, as the text s a ys, then the varia tion in the m e dian (or som e higher percentile, if all the

m e dians are zero) is of much m o re interest th an th e outliers, w h ich is all o n e can see o n this plot. Plot the m e dians on a scale that can be read, as in Figs. 2- 12 – 2-15, rather than

emphasizing the m eaningless noise in the outliers . Maybe a log scale would work better. The plot is not useful as curre ntly configured. Also, it’s no t clear what the caption m eans by ‘all cities in focus. ’ It seem s to imply that th ese ar e the c ities inc l ude d in the Fig s

. 2.1-2.6, but the text says it summ arizes all the da ta in AQS, so that should be clarified.

2-26 The description of the 5-m i nute sa mple data is s t ill lack ing. The text and Tables 2-6 and 2-7 don’t agree. For example, Ta ble 2-6 has 80 m oni tors reporting 5-m i n averages and Table 2-7 lists 16 m o nitors reporting all 12 5-m i nute values. The text reports that 108 m o nitors reported 5- m i n averages and 15 monitors reported all 12 values. These need to be reconciled.

2-34 line 6 Annex Section B-6 should be B-3

2-46 line 27 A m onitoring s ite at an elevation of 250 m above street level? Is this correct?

2-47 line 1 ...should ‘outdoor’ be ‘personal’ inste a d ? Am bient concentr ation s are outdoor concentrations.

2-56 line 19 or -> for

2-63 line 5 delete ‘of’

5-2 lines 5-6 Transport of SO2 plum e s from Asia and Europe really wasn’t discussed in the previous sect ions, so this statem e n t doesn ’t belong in the conclusions unless it is supported by the earlier text.

5-2 lines 15-18 Here’s another dism issa l of the 5-m i n data as unimportant for determ ining concentrations and exposures at s hort tim e durations. This just doesn’t make sense. Perhaps the data are insufficient to m a ke sweeping generalizations about national exposure, but they certainly are useful and vali d, and their temporal variability is exactly what m a kes them valuable and why we collected them in the first place. A m o re reasonable statem ent here would be that the existing 5-m i nute data are not adequate to assess exposure on a national scale – but th en, neither are the hour ly data.

5-2 line 24 rem ove the 7 after exposures

195-3 lines 8-11 This statem ent is correct , but would be m u ch stronger if the 5-

m i nute SO2 concentrations had actually b een summ arized in this docum ent.

20Dr. Patric k Kinney

Comm ents on SOx ISA – 2nd Draft

One general concern I have relates to the way the ISA interp re ts the pub lic health relevance of concentrations below those studied in the hum an clinical studies, i.e., 0.2-0.4
ppm

. As noted in the IS A, these studies look at effects in groups of people who do not represent the full range of su sceptibilities present in the general population. In addition, clinical studies study very sm all numbers of subjects as comp ared with the population exposed to ambient concentrations. These tw o issues lim it the power of clinical studies to quantify exposure-response relationships at ambient-relevant c oncentrations. Given this, it is inc o rrec t to a s s u m e , as EPA seem s to do in the cu r r ent ISA, th at the lowestobserved effect concentration represents a threshold below which no effects occu r. After all, we are concerned with protecting the US population, which cont ains over six orders of m a gnitude m o re people than have been st ud ied in a typ i cal clin ical stud y. A better way to inte rp ret the exp o sure- r espo nse resu lts f r o m clinica l s t udies is th at they prov id e points on a exposure-response function that extends down to zero ppb. T h is concept should be discussed in the ISA, providing a better foundation for its application in the health risk a ssessm ent in the REA. It also would help to bridge the large gap that currently exists between the exposure levels at which responses/associations are observed in clinical/epidem i ologic studies.

p. 1-7, line 12: change “occur” to “exist” p. 1-7, line 24: change “with ” to “with respe c t to ” p. 1-8, line 2: it should be noted as w e ll that control for confounders, whether by adjustm e nt or stratification, is only successf ul when the conf ounder is well m easured. This point is often overlooked. p. 1-8, first f u ll paragraph: Needs to be rewo rked. It' s not clear whether you' re talking about confounders, the exposure of interest, or both. It seems to change f r om one sentence to the next. p. 1-8, second full paragraph: To the lay re ader, it m a y be unclear what you m ean by covariates as opposed to confounders here. Also, this section on confounders would benefit from a clear definiti on of confounding at the outset. p. 1-13, line 13, insert “controlled hum a n e xposure studies,” before “epidem iological” p. 1-14, box on causality categories, in the row labeled “inadequate to infer the
presenc e ...” , inser t “qua ntity, ” bef o r e “quality” p. 2-8, section 2.4. This section should start o ff with an intro paragraph stating purpose and approach of the section. The very techni cal m i nutia of the initial text is off-putting as written. p. 2-8, line 17: need to insert definitions of the three geograph i c scales in term s of kilom e ter ranges or such. p. 2-9 through 2-11, line 2: this whole secti on reads like a guidance m a nual for setting up

a m onitoring station. I don' t think we need that here. Can' t we assum e t h at existing monitors satisfy these criteria, and move on? Once sentence would be enough to say that. p. 2-9, line 3: define “m onitoring path”, or better yet, delete this whole discussion.

21p. 2-10, line 6: I don’t thi nk the “open path” analyzer was de fined or described earlier. Please add that. How relevant is this? Is this an EPA e quivalent m e thod? If not, why discuss? p. 2-11, section 2.4.2: It would be better to st art off by presenting descriptive information and summ a r y statistics on the national data (e.g., table 2-4) rather than f o cusing on six particular states. Rationale for these six st ates is not sufficiently clear. Please expand. p. 2-21, Figure 2-10: a sim ila r m a p showing emissions at U S ports would be a very useful addition. p. 2-21, line 10: what is “diel”? p. 2-22, Table 2-4: This tabl e should be referred to repe atedly throughout subsequent sections, esp ecially chap ter 4. p. 2-23, figure 2-11: not clear what is m eant by “cities in focus” p. 2-32 and vicinity: I was surpri sed not to see any data from the 5-m i n so2 results. Why

m e ntion it here if no data are to be show n? Must explain why data are not shown. p. 2-38 and later in Section 2.5: The uncertainti es are discussed extensively, but are never summarized quantitatively in any way. p. 2-57, line 9 and elsew h ere: shou ld be beta hat, not beta. p. 2-57, line 19: add text on effect of m easure m ent error on S E (beta hat) p. 2-58, line 5: spelling of physicochem i cal p. 3-25, line 15: please provi de a quantitative m easure of how prevalent these observations are. e.g., w h at fraction of 10 m i n avgs are above 0.4? the term "som etimes" could be m i s-interpreted as som e thing like 10 -20%. Reality is probably m a ny orders of

m a gnitude lower than that. p. 3-39, line 13, sentence starting “a st udy conducted” needs gramm a r fix. p. 3-43, line 4: state range of ppb for which exces s risk is calculated here, and put this range into the contex t of SD of a m bient 24-hour averages. p. 3-44, figure 3-8 and f o llowing text: I’m troubled that there are no st udies reported here that included PM2.5 as a co-pollutant. This om ission is an important caveat that should constrain any conclusions regarding robustness. Especially so given the dism issal of the long-term mortality resu lts for SO2 on th e bas i s o f concerns o v er sulfate PM2.5 confounding. p. 3-45, lines 13-18: This seem s too glib. I don’t agree that c oherence and biological plausibility are satisfied wh en com p aring cham ber results at 200-600 ppb and epi results are for am bient levels two orders of m a gnit ude lower. Need to include this caveat. p. 3-55, lines 16 to 25: T h is section needs to acknowledge the expos ure levels observed on average in epi studies, in m e trics equivalent to those used in ch am ber studies, e.g., 1- hr averages – noting m eans, sds, 95th percen tiles etc. This is done for the cham ber results but f o r som e reason is ignored when describing the epi findings . Table 2-4 is the relevant reference. p. 4-1, sentence on lines 20-23. This sentence is f a lse. It is not true that most epi studies evaluate whether there is a threshold

. Fe w if any epi studies ev aluate that question directly. Please edit. p. 4-3, Figure 4-1: indicate in footnote which of these resu lts are statistica lly sign if ica n t. p. 4-4, section 4.1.2: in linking the cham ber findi ngs with the epi findings, it is im portant to com p are the dosim etry in at least a se m i -quantitative way, taking into account the differences in exposure concentrations and activity levels.

22p. 4-4, line 10: change “was” to “could not be distinguished from ” Th e key point is that there is ve ry lim ited power to f o rm ally test whe t h e r som e thing is lin ear o r not. Failu re to reject linearity isn’t equivalent to “o bserving that the relationship was linear” p. 4-5, lines 8-10: this is a good example of the kind of c oncentration cross-referencing that I was lo oking for ea rlier. p. 4-6, Figure 4-4: tell us which of these resu lts are statistically significant, or better yet, provide conf idence intervals at each point on th e curve. OK to lim it to on e lag to simp lify display since they all say roughly sam e thing. p. 4-9, line 4: insert quantit ative LOD (e.g., 3 ppb) in pare nthesis after “detection” p. 4-9, lines 13-14: again the issue of “obs erving that the relationship was linear” p. 4-17, Figure 4-6: throughout the docum e nt , EPA concludes that ED visits and hospitalizations are as so ciated with SO2 for children and older adults. T h is doesn’t

com e through very clearly from this figure. Can the results for younger adults be added? Can histogram s be created of the RRs with in each age range? This would provide stronger backup for EPA’s conclusions a bout age-related effect m odification. p. 4-19, line 19: Edit grammar. As stated, it suggests that m o st st udies exam ine effect modification by SES, whic h is clearly untrue. p. 4-22, lines 19-27: need to include the fact that these findings ar e observed only with heavy exercise. Then later you need to esti m a te fraction of asthm a tics who spend tim e at those exertion levels, and also the fraction of time that people are exposed to these

am bient levels. Both are needed for risk assessm e nt discussions that follow. p. 4-23, line 9: this is obvious place to insert 1-2 paragra phs discussing the fraction of relev a nt exp o sure lev e ls and exertion levels experienced by s e nsitiv e subg roups. p. 4-23, line 16: risk only occurs with exposure, so need to discuss exposures here too.

23Dr. Steven Kleeberger

Comm ents on SOx 2 nd Draft ISA

3. In the revision, we reduced redundancy, added summary sections and reorganized Chapter 3. In addition, discussions on pot ential confounding by and interactions with copollutants have been added. The 2nd draft ISA also includes additional analyses of individual-level data from hum a n clinical studies (Secti ons 3.1.3. and 4.1.1) that builds upon the analysis included in the 1994 S upplem e n t to the Second Addendum

. The toxicology sections were reorganized to focus on studies using m o re relevant concentrations of SO 2 and sections were added to be tter discuss m ode of action and potential particle-SO 2 interactions. We are requesti ng CASAC review specifically on these an alys es as well as on the in teg r ation of the overall evid ence from the hum an clin ical, anim al toxicolo gical, and ep idem iologic a l stud ies.

Overall, the reorganized Chapter 3 is gr eatly im proved over the previous version. In particular, the following aspect s o f the Chapte r were usef u l:

 Summ ary of findings from the previous re view – these prov id e m u ch needed and useful reference points to enable evaluation of the m o re current investigations.

 Redundancy was largely elim inated, though so m e repetition rem a ins that could be edited or removed.

 Additional individual-level data (i.e. speci fic numbers of individuals in response groups) enabled better evaluation of betw een-individual varia tion and the impact on inte rpre ta tion of resu lts.

 Re m oval of anim al studies that used SO 2 concentrations that had questionable environm ental relevance was appropriate , though som e re m a in that likely could also be rem o ved.

 The end-section summ aries were very us eful and largely presented a reasonable evaluation o f the literatu r e with resp ect to we igh t of evidenc e f o r causal determ inatio n.

 Incorporation of the effe cts of SOx interv ention and subsequent change in health
outcom e s into evaluation of causality was appropriate and useful.

Additiona l Comm ents:

While it m a y be argued that SO2/particle interactions should be included in the ISA docum ent, the case was m a de in the REA that the curren t rev i ew of the SO2 NAAQS would focus on gaseous species of sulf ur oxides and not consider health effects directly asso ciated with part iculate sulfur oxide species. These species and their health ef

f

ects inste a d will be re viewed in th e PM docum ent. However, one of th e sections in the

24SO2 document (3.1.5) includes effects of SO2 la yered on particles and sulfite aerosols. I did not find the section f it particularly well with the rest of th e docum ent and raised additional questions that could not be answered, or m a y have been answered in the P M docum ent. My recommendation would be to elim inate this section.

The REA clearly differentiates between long-term exposure (m onths to years), short-term exposures (hours to days), and short-term peak exposures (5-10 m i nutes) throughout the docum ent, especial ly beginning w ith the Health Effects chapter (part 4). The ISA differentiates prim arily betw een l ong-term exposure and short-term exposures, with the short-term peak exposures embedde d in the latter (e.g. section 3.1.3). An introductory statem ent or sm all paragraph plac ed at the beginning of the m a jor sections of Chapter 3 (e.g. 3.1) w h ich define the dist inctio n m a y help the reader to place the studies in th e intend ed p e rspec tive.

Minor

P 3-4, line 5: delete “a” from “presenting a m o re details”?

P 3-13, lines 26 and 28: is it correct to s uggest that SO2 m a y elicit an allergic inflamm a tor y response? SO2 is not an allergen.

P 3-17, lines 9-21. I am not sure that this sect ion really provides “b iological plausibility for the effects of SO2 on respiratory symp to m s i n hum a ns”. The relevance of MUC5AC expression induced by SO2 using in vitro m odels and in rats exposed repeatedly to 2 ppm SO2 to respiratory sym p tom s in humans is que stionable, and presenting these prelim inary studies is no t necess a ry.

P 3-103, line 10. “is” should be “are”?

25Dr. Timothy Larson

Comm ents on SOx ISA 2 nd Draft

Chapter 2:

Section 2.4 is reorganized and shortened with a more appropriate focus on interurban variability. Tables 2-4 and 2-5 are p a rticula r ly u s ef ul in th is regard. The inform ation on correlations with other pollutant s is obviously limited by the l ack of co-located m onitors. The discussion of the available 5-m i nute data is an important addition to the chapter, but it is v e ry b r ief

, given the im portance of this data in the REA. W e are lef t with a
statem ent that these data are “very difficu lt to use precisely”, without knowing exactly what that m eans. Do th e authors m ean the m easurem ents are difficult to use becaus e they are in accurate or that they are accurate but are hig h ly variable across tim e and space?

Based on my prior review comm ents, I note that on page 2-52 the statem ent is still m a de that “when personal exposure concentrati ons are above detection lim its, a reasonably strong association is observed between persona l exposures and am bient concentrations”. This statem ent is based prim arily on the resu lts of one study done in one city over two seasons. In addition, there are no studies th at have assessed the relationship between community exposures and central site con centrations of SO2. Appropriately, the summary chapter h a s been changed to place th e s i gnificance of these resu lts (o r lack thereof) in the context of epidem iological study design and now a voids repeating the
statem ent on page 2-52.

Other comments:

On page 3-52 the statem ent is m a de that “aero sol particles act as car riers and deliver S O 2 to the lower respirato r y tract”. The evidence supporting this is base d primarily on studies done on rats exposed to relatively high levels (1 to 10 m illigram s per cubic m e ter) of freshly generated zinc, copper or carbon black particles in combination w ith SO2. These studies report a synergistic e ffect of SO2 in combination with the particles and m easure sulfate and/or sulfuric acid coatings on the particles exposed to SO2 as a possible explanation for the interaction. There is one study listed on page E-17 by Clarke et al (2000- it is not in the referen ce list but I assum e it is the one in Inhalation Toxicology v12, pp169-186) that is summarized as seeing synergistic effects at m o re realistic levels of sulfate particles (~20 m i cr ogram s per cubic meter). However, to produce these particles in the lab required 1 m illigram per cubic m e ter of carbon black particles and 1
ppm SO2 at 85% RH. In summary, the studies listed in support of the statem ent on page 3-52 were done at very high levels relati ve to contemporary atm o spheric SO2 levels (effects in the Clark et al study were seen af ter 5 to 6 days of exposure to 1 to 10 ppm whereas th e ISA summ ar y of typi cal SO2 levels o v er th is av eraging period are typically below 0.01 ppm ; sim ilarly, the PM levels were 1 -10 m g / m 3 whereas typical PM levels of fine carbon are 1-10 ug/m 3). Although th ese studies do support the notion of an increased response to sulfate-co ated particles, they do not support the summ ary statement on page 5-11 that “the synergism observed with com b ined exposure to S O 2 and PM in

26the anim al toxicological studies provides supportive evidence for the SO2-related respirato r y effects observed under ambient cond iti ons in th e epidem iological studies”. In f

a irness, th is is pres ented in the docu m ent as an interpr e ta tion rathe rthan a conclus i on

. Given the unrealistically high SO2 and PM leve ls used in th e anim al stu d ies (f ac tor of 100 to 1000 relative to realistic am bient levels) , its hard to claim that these studies provide supportive eviden ce for the relev a nt ep idem iological studies.

27Dr. Ted Ru ssell

Comm ents on SOx ISA -- 2 nd Draft

The 2 nd Draft ISA is an improvem e nt over the fi rst, though could still benefit from som e pointed analyses, particularly in light of the direction of the associated RWA. In particular, the REA deals predom inately with assessing the exposure and risks associated with 5-m i nute average S O 2 concentrations, a nd h o w such concentration s are associated with 1-hr average levels. Thus, this section of the ISA could be im proved. In particular, added analysis of the structures of 5-m i nute and 1-hr average concentrations, and how the two correlate. In particular, the conc entra tions th at le ad to the 5-m i nute m a xi m u m a nd 1- hr levels are from the sam e distributions , and thus are strongly linked. H a ving the correlation structure would be useful to th e staff developing the REA. Indeed, such inf o rm ation could help stream line the i r chap ter on air quality data. At pres ent, the ISA has little analysis of the f i ve-m inute results. It is interes ting to note tha t th e curr ent IS A says that it is “very difficult to use (these data) precisely”, yet the REA does significant analysis of the data (and I am not su re what they m ean by “precisely”).

I would think that SO2 concentrations bei ng observed at a m o nitor will tend to follow a log-norm a l distribution, whether one consider s five-m inute or one-hour average values, and that the two distributions would have a sim i lar m ean, but that the GSD would differ. (The geom etric m eans of the two would not ne cessarily be th e sam e , given that the onehour average is an arithm etic average). T hus, this section should consider presenting concentratio n statistics in term s of the geom etric averages an d standard d e viations (G SD) (they will need to address how the be low detec tio n lim it value s are trea ted ) . From this, one could assess how the GSD’s of the five-m inute and one-hour levels correlate, as well as how the five-m inute and one-hour m a xi m u ms correlate. One m i ght think that the fivem i nute m a ximum can be well approxim ated as a function of the one-hour m a xi m u m a nd associated G S D.

Page 1-1, line 12: m onom e ric, gaseous, sulfur species. Page 1-9, line 18: The science is not uncertain... the results contain uncertainty. Page 2-3, lin e 13: The s u lfuric acid will m ove to a condensed, not neces sarily aqueo u s, phase. Further, it is not rem oved. Page 2-3, line 18: W h at about sulfate? Page 2-4, lines 20 on. This section is a abit confusing. They state that most of the oxidation is via aqueous phase chem istry, then us e the gas

- ph ase lifetim e to calculate an overall lifetim e . Again, it would be best if they used resu lts from a US-based set of sim u lations to addres s th e f o rm ation, f a te and lif e tim e. Section 2-3: Again, provide a straigh t forward answer to the q u estion as to whether

sam p ler issues im pact the issues under consid eration here, and I susp ect the answer is no. Table 2-4: Define units, m a ke the caption m o re com p lete. Page 2-25, line 9: I still think you m e an three summ er m onths, not seasons. Figure 2-11 : This f i gure is still of limited u tilit y. It is impossible to see the frequency of observations at the low end. Pr ovide a plot that actually pr ovides such inf o rm ation. All this figure does, really, is indicate an aver age (which is too low to discern) and the

28m a xi m u ms. Use a log scale. Better yet, give a table of arithm e tic m ean, geom etric m e an,

m a xi m u m, m i ni m u m and geom etric standard deviation. If you want, you can add a trad ition a l S D , though I would state this is less helpful. I was pleased to see Sections 3.1.5.2.1-3.1.5.2.5 d ealing with SO2-par ticle interactions, though none of these dealt w ith the dynam i cs of SO 2 uptake, and evaded the question of how likely such m echanism s may be in the at m o s phere. Uptake of SO2 on atm o spheric particles is likely very slow, as is seen by the ability f o r SO2 and particles to coexist in the atm o sphere for long am ounts of t i m e . Fu rther, the studies’ us e rather artificial surfaces th at would be considered m u ch m o re reactiv e and p o tentially ab sorbing th an atm o spheric aerosols. A further lim itation to how the results in these sections m a y be applied in this assessm ent is that the products of the in teraction between SO2 and the particles would be m onitored as part of the PM matrix, and be regulated as PM. W h ile there is a significant am ount of sulfate in PM, which can be explained by gas and aqueous phase oxidation of SO2, there is rather little sulf ite, suggesting th at particles would provide little avenue as a m echanism to transpor t sig n if icant qua ntities of SO2 deeper in to the lung. S O 2 has a low Henry’s law constant, so little will be stored as sulfite in the aqueous phase in a naturally o ccurring aerosol. This section should be more critica l in its assessm ent of the importance of such processes. At present, there is no indication from observation of atm o s pheric aerosols that the studies discussed are relevant, and, conversely, there is ample eviden ce to suggest what is found is lim ited to laboratory generated aerosols that are then exposed to extremely high levels of SO2.

Summ ary and Conclusions:

Page 5-1, line 25: I would add “... facilities , though em issions from tall stacks m a y have a lesser im pact on high concentrations at ground level due to diffusion.”

5-11, line 2: Here, it says that effect estim ates were found to be robust w h en using 2- pollutant m o dels, but in Chapter 3, F i g 3-8, sugg est th at th e significan ce of the SO2 effect decreases when including PM10, som e ti mes leading to its being insignificantly different from zero? I probably also take excep tio n to the con c lusions in Chapter 3 dealing with their interpr e tation of th e m u lti-pollutant a ssess m e nt.

In response to the Charge Questions:

1. The framework for causal determination and judging the overall weight of evidence, is presented in Chapter 1. Is this the appropriate approach? Is it appropriately applied in the case of SO x ? How could the framework or its application be refined?

The curren t version is improved. I will leave th e adequacy issue to tho s e with a m o re appropriate expertise.

2. The discussion of the at mospheric chemistry o f

SO x has been expanded to provide a better characterization of the sp atial heterogeneity of urban SO 2 concentrations and correlations of SO 2 with other pollutants. We also included new sections describing the regulatory network and s iting criteria with maps of SO 2 and other monitors. A

29brief section describing the available 5-minute SO 2 data was also included. In addition, the relationships between out door, indoor, and personal exposure to SO 2 were clarified with additional details on sources of exposure error. Have these revisions to Chapter 2 improved its assessm ent of the currently available scientific knowledge on atmospheric sciences and ex posure and its relevan ce to the evaluation of human health effects presented in later chapters?

W h ile the ne w chapter is, indeed, im proved, as dis c ussed abov e ther e are still som e further needs. In particular, the section on 5-m i nute averages is inadequate given the reliance of the REA on 5 m i nute data. This chapter should have CDFs for 1-hour and associated 5-m i nute SO2 data, as w e ll as a characterization of the correlations. The chapter would still benefit from a table of sources and their amounts. Given the discussion in Sections 3.1.5.2.1-3.1.5.2.5, this ch apter should provide a scientific foundation for the relevance of the proposed m e c h anism s and how they are supported by observational evidence in the atm o sphere.

3. In the revision, we reduced redundan cy, added summary sections and reorganized Chapter 3. In addition, d i scuss i ons o n poten tial confounding by and inter a ctions with copollu tants have been a dded. The 2nd draft ISA also includes addition a l analyses o f individual-level data from human clinical studies (S ections 3.1.3. and 4.1.1) that builds upon the analysis included in th e 1994 Supplement to the Second A ddendum. The toxico lo gy sections were reorganized to focus on st udies using more relevant concentrations of SO 2 and sections were added to better discuss mode of action and potential particle-SO 2 interactions. We are requesting CASA C review specifically on these ana lys e s as well as on the in teg r ati on of the overall evidence from the human clinical, animal toxi cological, and epidemiological studies.

As discussed above, Sections 3.1.5.2.1-3.1.5.2.5 should be assessed for their likely im portance in the atm o sphere and to resulti ng exposures. Such sections should not be added without appropriate foundation and disc ussion of how likely they are to be of actual importance.

4. The section on concentration-response relationships in C hapter 4 was reorganized and revised to include analysis of individua l-level data from the human clinical studies and some additiona l dis c ussion of the diffic ulties of discernin g a threshold in population

- level da ta. In addition, r evis i ons wer e made to better characterize group s likely to b e s u sceptible o r vulnerab le to SO x and the potential size of the population at risk fo r SO x -related health effects. Finally, revisions were made to reduce redundancy with material presented in C hapter 3. Have the revisions made to Chapter 4 improved the characterization of the potential public health impact of SO x exposure?

5. Revisions were made to better integrat e findings from atmospheric sciences, ambient air data analyses, exposure assessm ent, dos imetry, and health evidence in Chapter 5. To what extent do these findings suppor t conclusions regarding causality of SO x relate d

30health effects at relevant exposures?

The greatly stream lined Chapter 5 is an im pr ovem e nt. I will take issue with the us e of the stud ies c ited sugg esting that the p a rticle s act as ways to deliver SO2 significantly more efficiently to the deeperlung, and that the sulfur asso ciated with th e particles is predom inantly sulfate form ed from chem ical r eactions in the atm o sphere, and very little is from SO2 interacting dire ctly with dry part ic le s. The m o lecular k i netic s and
atm o spheric observations both argue against this.

31Dr. Kent Pinkerton

Comm ents on Sox ISA – 2 nd Draft

General Co mments : The second external review dr aft of the integrated science

assessm ent docum ent f o r Sulf ur Oxides/Heal th Criteria is much improved over the 1 st draft. The chapters are well organized and l ogical. The regulatory history for sulfur oxides is interesting to observe with no changes since 1969, although com m e nts were solicited for a 1 hour standard of 0.4 ppm as well as a 5 m i nute standard of 0.60 ppm SO 2 in 1988. The current standard for sulfur oxides rem a ins at 0.14 ppm averaged over a 24 hour period, not to be ex ceeded m o re than once p e r year and 0.030 ppm annual arithm e tic

m ean with SO 2 as the in dicato r

.

The authors of the docum ent have focused each chapter to address th e most relevan t issues and have presented a rather thorough a nd updated review of the literature since the most salient features of past reports. New publications presented in the 2 nd draft ISA are highly appropriate, well-presented with a ba lanced interpretation. The presentation of positiv e and negativ e stu d ies is we ll balanced with possible in terpr e ta tions provided based on a solid scientific basis.

Question 4: The section on concentration-respon se relationships in Chapter 4 was reorganized and revised to in clude analysis of individual- level data from the hum an clin ical stud ies and som e additional discuss i on o f the dif f i culties of dis cer ning a th res hold in population-level data. In a ddition, revisions were m a de to better characterize groups likely to be susceptible or vulnerable to S ox and the potential size of the population at risk for Sox-related health effects. Fina lly, revisions were m a de to reduce redundancy with m a terial presented in Chapter 3. Have the revisions m a de to Chapter 4 improved the characterization of the po tential public health impact of Sox exposure?

Response:

The concentration-response relationships ar e clearly presented in Chapter 4. Hum a n clin ical stud ies prov ide c o m p elling d a ta to d e m o nstra t e SO 2 -induced decrem ents in lung function (FE V 1 ) and spec if ic airway r e sistance (s Raw) in asth m a tics f o llowing lim ited (10 m i nute) exposure to SO 2 . An increasing proportion of asthm a tic responders to increasing levels of SO 2 further confirm a strong concentration-response.

Epidem iological studies, alt hough less definitive than hum an clinical studies, also provide strong evidence of in creasing asthm a hospitalizatio ns with increasing 1-hour

ma x i mu m S O 2 levels ranging from 0.20 to 0.60 ppm

. An i m portant point to em phasize in both the hum a n clinical and epidem iological st u d ies is the o b servation that sign if ica n t effects were noted at SO 2 levels beginning slightly above 0.20 ppm

.

Based on the hum an clinical and epidem iol ogical study findings reported in Chapter 4, it appears the approach to be im ple m e n ted in the REA by the EPA of thes e findings is to use 0.4 to 0.6 ppm as the beginning level for co nsideration to derive an appropriate level

32of safety to public health. Although data (e specially the human clin ical study) shows an increased response as S O 2 levels are increased in a cl assical a concentration-response profile, a strong rationale needs to be m a de for not beginning at a m a xi mal SO 2 concentration of 0.20 ppm.

Once again, sim ilarities between hum a n clini cal and epidem iological studies should be

emphasized, although I would agree that the hu m a n clinical studies provide the m o st

comp elling evidence in consideratio ns for setting the standard for SO 2
. The difficulty in establishing a threshold in population-level data is well presented in Chapter 4. Hum a n clinical studi es a r e likely to b e the bes t source for setting risk levels, but epidem iological studies continue to provid e strong supportive evidence as well. It is questionable whether one should consider non-linear concen tration-response relationships to SO 2 levels, based on epidem iological studies, especially those studies illus t r a ted in f i gures 4-4 and 4-5. These stud ies d e m onstrate e f f

ects begin n ing in th e 0 .2 to 0.3 ppm l e vel. I would suggest (as som e what already stated in the text of Chapter 4) it is im portant to not over-interpr et these epidem iological find ings as being non-linear. To do so, would also require an explanation in the S c hwartz et al study (1994) (Figure 4-5) for a negative odds ratio at a low level (0.10 ppm ) of SO 2 and a non-linear increase in the odds ratio as levels of SO 2 increase to 0.4 ppm

. Chapter 3 co ntains a comprehensiv e o v erview th e scien tif ic literatu re a l on g with a

com p lete and thorough review of new studies published since the pr evious review. The presentation and stated interpretation and conc lus i ons of this data in g e ne ral a r e log i c a l and balanced. The summ aries found at the e nd of each section in Chapter 3 are h e lpful

rem i nders and a reasonable and rational reflection of the section conclusions.

Chapter 4 is written to ad dress c r itica l issues of public health impact as discussed above. The chapter contents are presented in such a fa shion to utiliz e critic al data presented in Chapter 3 without being redundant. The defi nition and significance of susceptible and vulnerable populations is discussed. These are important factors that require a clear explanation in order to identif y the appropriate populations at risk. Should these two populations identified as “susceptible” and “ vulnerable” have overlap, is this also a critical com ponent in estim a ting the appropr iate size of the population at risk.

Excellen t ex am ples of epidem iological stud ies are presented to furthe r co nf irm sensitivity of

children with asthm a to SO 2 . Similar sens itiv ity in adu lts has not been found. Genetic factors related to health outcom e s were also co n s idered with regard to air pollutants as an im portant factor to consider in future studies. A study by W i nterton and colleagues (2001) has f ound a significan t association between SO 2 and the hom ozygous wild-type allele for T N F-alpha.

W ithin chapter 4 is also presented a nu m b er of studies to exam ine age-related susceptibility with a good balance of studies and outcom e s. The tables and figures throughout the chapter are highly complim entary to the text. To estim ate the size of the

33population at risk is an important determ inant, but will n eed to incorporate the appropriate param e ters.

In summ ary, this is an ex cellent chap ter. Since the standard has not changed since its original inception in 1969-71, if the potential decision by EP A in the REA is to suggest changes in the standard to prom ulgate a 5-10 m i nute peak or 1-hour m a xim a l level of SO 2 , this potential to recomm end a very differe nt standard from the current standard needs to be clea rly ju stif ied in this c h apter o rin the REA.

Specific co mments: Page 4-2, line 26: please state the m eaning of sRaw in the text

34Dr. Edw a rd M. Postlethw a it

Comm ents on SOx ISA – 2 nd Draft

The second draft of the SO x ISA is clearly improved. Sugge sted points for consideration include :

1. Much of the docum ent focuses on the poten tial im pacts of short ter m , relatively higher concentration exposures. In this regard , it is impo rtant to describe and/or illus t r a te th e charac te ristics of sh ort te rm spikes. This m a y be important f o r exposure/risk predictions since it is assu m e d that 5-10 m i nute exposures will be modeled as steady state exposure co nditions but in the real world such spikes m a y, for example, be very sh arp rather than the square wave exposure patterns that are generally employed in most hum a n clin ical inv e stig ation s

.

2. Do the tables which include comp ilations of relative risks com puted from population studies include points which are not statistically significan t? If so, then there m a y be an unin t entional b i as in rep r esen tin g poten tia l health im pacts. If non e sign if icant results are to be presented, they should be identif i ed as suc h to app r opr iate ly inf o rm the reader.

3. W h ile the h u m a n clinic al stud ies of as thm a tics show apparent thresholds at SO 2 lev e ls between 0.4 and 0.6 ppm, other data m a y s uggest that som e individuals m a y respond at lower co ncentration s . Thus it is reco mm ended tha t p r e d ictive e s tim ates utiliz e concentrations below the proposed benchm ark 0.4 ppm level.

4. The above highlights an appreciable challe nge for conducting risk estim a tes in that

som e popul ation studies suggest ef fects o ccur at levels well below those observed during clinical studies. The ISA would clearly be strengthened by an improved integration/synthesis regarding the potentia l genesis of effec t s threshold differences, especially since the chap ter on dosim etry clearly describ e s th at > 90% of inhaled SO 2 is scrubbed in the upper airw ays so that during environm entally relevant exposures only very sm all a m ounts of SO 2 would penetrate to anat om ic regions involved in bronchoconstrictive events. Thus at leas t a n attemp t to clar if y the apparen t discrepancies is warranted.

5. The concluding language in the various heal th effects sections relating exposures to the various biological endpoints of interest would be stre ngthened by more internal consistency. For example, it is stated th at there is sufficient evid ence “to infer a causal relationship betw een respiratory m o rbidity and short-term exposure to SO 2 ”, which is unequivocal based on clinical studies. However, in other sectio ns statem ents regard ing causality have the caveat “at cu rrent am bient levels. ” Thus, whi l e asthm a tics, and likely most individuals, will respond at som e threshold exposure level, wheth e r this occur s at a m bient levels is no t cons istently addres sed. Becaus e of the dearth o f m o re current data and th e confounding associated with multipo llu tant

35exposures in population studies, the ISA w ould benefit by more thorough discussion of

the poten tia l f o r SO 2 to induce biological effects vers us those effects that are/can be detected under am bient conditions.

36Dr. Jonathan M. Samet

Comm ents on SOx 2nd Draft ISA

General Comments :

Overview :

This second draft Integrated Science Assessm ent (ISA) has been re drafted following the initial review by CASAC. Al ong with the draft ISA for N itrogen Oxides, it represents the second use of the new evidence review approach by the E nvironm ental Protection Agency. As such, it remains critical that a u s ef ul m odel be established for future reviews.

In this regard, I still find the second draft ISA to be defi cient. W h ile ch anges have been

m a de, the approach to evidence identi fication, review, and synthesis rem a ins inadequately specified. In the revised Ch apter 1, while the A g ency has begun to m o re f

o rm ally set out cr ite ria f o r eviden ce evaluation and standard approaches for clas sifyin g the strength of evidence f o r causatio n, the ove r a ll approa ch still n eeds dev e lopm ent and its application in the subseque nt chapters of the ISA is not sufficiently thoughtful. My responses to the charge questions follow:

Question 1 :

This question asks whether the fram ework set ou t in Chapte r 1 is appropriate and adequately applied, and whether th e Agency’s ap proach for causal inference needs to be strengthened. The Agency, in developing its approach, has relied on a num b er of recent reports that offer m odels, including the appr oach taken in the Surgeon General’s Reports and the conceptual fram ework set out in th e recen t Institu te of Medicine d o cum e nt, Improving the Presumptive Disability Decision-Making Process for Veterans . These docum ents along with the others that are cited do provide useful approaches. The Agency’s ad option of a five-level set of descriptors of strengt h of evidence is appropriate and should prove useful for decision-m a king based on the degree of certainty provided by scientific evidence considered. Through its appl ication, the Agency will be able to refine the rev i ew and synthesis process and

, in particu l ar, set p r eced ents for resp onding to evidence reaching different levels of certa inty for causation. For example, would evidence reaching the “suggestive” level be a sufficient foundation for altering a NAAQS?

There are still lim itations of Chapter 1, howev er. The discussion of association versus causation is not well formulated and the autho r s are not clear in disc ussing key concepts that affect interpretation of epidem iological data. For example, confounding and effect modification are add r ess e d rath er su perficially, as is m easurem ent error. I urge the staff to continue to refine this m a terial, because it will becom e a model for future ISAs. The authors com m e nt on the com p lexity of determ inants of health and of response to an environm ental agent, such as sulfur dioxide . However, their approach to doing so is lim ited and Figure 1-1 is presente d with little explanation.

37The discussion of uncertainty is brief and n eeds expansion. A m o re system atic approach to describing uncertainty would be usef ul, both around determ ination of causation and with regard to the quantificat ion of effect. This importantissue is handled in only one
page.

I was concerned by the application of the a pproach for causal inference in subsequent chapters. T h e discussion is lim ited around evid ence synthesis, particularly in Chapter 3. There needs to be a be tte r temp late f o r a ssuring standardization of discussion of the streng th of evidence.

Charge Question 4 :

The revised Chapter 4 adequately sets out the qu a n titativ e inf o rm ation f r om the hum an clinical studies. The plot s are clear in showing the obs erved concentration-response relationships. The epidem iological data ar e also described, although the findings cannot be so readily summarized.

The chapter offers definitions of “suscep tib le” an d “vulnerable” that need som e strengthening. Is a susceptible population as defined or one that has a steeper exposureresponse relationship than a non-susceptible population? The definition given here

emphasizes response at a lower concentra tion than in the general population. The distinction between susc eptibility and vulnerability lies in a greater biological response for susceptible individuals and a greater risk for exposure (higher exposure? ) in a vulnerable population. Later in the chap ter this distinction becom e s blurred.

Specific Comments :

Page # Line # Comment

1-5 1 Need introduction here that a hi erarchy of evidence m a y be identified and that for som e pollutants hum an clinical studies m a y provide the
most comp e lling evidence, e.g., CO, but not for all, e.g., PM. 1-5 6 Delete “can” 1-5 8 A panel study is a cohort study 1-5 9 “...occasion a lly in epidem iology:” and offer the opportunity to investigate a change in exposure. 1-5 15 “species” and the m odel used 1-6 5 “The results are” delete and s ubstitute “observed risk represents” 1-6 8 The alternatives are chan ce and bias 1-6 8 “subjects in a population” usually volunteers 1-7 3 Random i zation needs better desc ription: of exposure (pollutant vs sham or of people (pollutant or sham ). 1-7 6 Delete rand om ness, substitu te “ t he r o le of chanc e”

38Page # Line # Comment 1

- 7 1 6 “Nutritional de ficits ” Such as ? 1-7 17 “from epidem iological studies” Not inferred from epi studies alone. 1

- 7 1 9 Delete s t atis tica l 1-7 24 Delete “with”, substitute of 1-7 25 Effect m odification can also be exam ined with m o dels 1-8 1 “possible mechanism s ” and the di stributions of these factors in the population under study. 1-8 4 “In m u ltivar iate analys es ...” true ? On what basis ? Ref e ren c e s ? 1-8 10 But not necessary 1-12 10 Delete “ t he absence of ”, Substitu te n o t m eeting 1-13 1 “recen t publications” All relev a nt? 1-14 19 “The comp l e x m o lecular and...” What does this m ean? 3-1 7 Delete “nature”, substitute role 3-1 21 May provide evidence 3-2 9 And to precisely characterize exposure/response 3-2 23 Delete “test”, not a test-an application 3

- 3 2 “thus, attem p ts results of m odels that attemp t to d i stingu ish 3-3 11 Delete errors, substitute problem s 3

- 3 1 4 Why? 3

- 3 2 2 “reliability” or v a l i d i t y ? 3-8 25 How were studies selected? 5-2 20 “led to the conclusion that it ” Substitute the evidence. 5

- 2 2 6 The, substitute An immediate response 5

- 2 2 7 “bronchoconstruction, this response is m e diated ” 5-3 1 Depending on concentration 5

- 3 8 “hum an clinical st udies (finding reporting of reporting respiratory

s y mp t o ms ) ” 5-3 12 “5-20%” Of asthm a tics 5-4 24 “internal coherence” What is this? 5-6 6 How do they provide plausibility? 5-9 12 “m uch unce r tainty rem a ins” W h at does this m ean? W h at kind of uncertainty ? 5-11 17 “Individuals in, substitute having a chronic” 5-12 4 “data support the finding ...” Not the proposed language

39Dr. Richard Schlesing er

Comm ents on SOx ISA – 2 nd Draft

Overall, the 2 nd draft improve s on the 1 st in integ r ating th e va rious d i sc iplines. Howev e r, there is s t ill room f

o r improvem e nt in som e of the section s as noted below. In m a ny cases, th e various d i sciplines a r e n o t rea lly in tegrated but rather separate discussions of each are just placed in th e sam e section. A true in tegration wo uld interweave the ep i w ith

m echanistic support from the controlled studies.

The inclusion of a section on m i xtures, i.e ., 3.1.5, is an improvem e nt, but it is not clear why that section was p l aced where it was. I think that a section on m i xtures and the potential f o r inte rac tio n rela ted to all hea lth outcom e s f r om SO2 f o r all exp o sur e scenarios should be d e veloped and placed at th e end of the ch apter p r io r to the Conclusions.

Table 5-3 is excellent and pr ovides a very nice summary ove rview of the conclusions of the ISA and com p arison to the p r evio us Criteria Docum e nt.
Specific Iss u es

1. Section 3.1.3 is titled, Respiratory E ffect s Associated with P eak Exposure. In reality, this is a discussion of studies that involve expos ures for 1 hr or less to single levels of SO2 without any base line in anim al and hum a n clinical evaluations. Thus, the use of the term peak m a y be m i sleading since this m a y imply som e higher level rela tive to s o m e lo wer baseline. This section should also be renum bered as follows:

3.1.3.1 Clinical S t udies

3.1.3.2 Anim al Studies

2. Section 3.1.4 discusses Epi st udies and this should be reflected in the section heading. Furtherm ore, lines 7-21 on page 3-17 should be m o ved to section 3.1.2.

3. Section 3.1.4.3 is an attempt to integrate anim al, hum a n clinical and epi studies.

4. Page 3-48, lines 15-17. T h e inconsistency m a y be due to the f act that the specific nature of the interaction m a y depend upon the specific co-pollutant.

5. Section 3.1.6 seem s to be out of place here. Perhaps the m a terial could be integrated into other sections.

406. Section 3.2. title should perhaps read “system i c” rather than “other.”

7. The conclusions in section 3.2.2.are not to tally consistent with the statem ents

m a de on page 3-59, lines 24-27. In one case, the evidence is noted as inconsistent while in the other it is noted to be inadequate.

8. On page 4-1, add “and vulnerable” f o llowing susceptible on line 10.

9. The comme nt on page 4-12, lines 1-2, that epi studies suggest that people with preexisting respiratory diseases are m o re suscep tible to effects from SO2 contradicts the comm ent on page 4-11, lines 12-13.

10. The sentence on lines 17-19 on page 4-20 is not clear.

41Dr. Christian Seigneur

Comm ents on SOx ISA – 2 nd Draft

Charge Question 2. Have these r e visions to Chapter 2 improved its as sessmen t of the currently available scientific knowledge on atmospheric sciences and exposure and its relevance to the evalua t ion of human health effects presented in later chapters?

The second version of the ISA for the health criteria of sulfur oxides shows significant im prove m e nts com p ared to the first draft ve rsion. Comm ents m a de last year on the discussion of the physico-chem ical processes th at govern the evolution of sulfur oxides in the atm o sphere have been addressed in this revised version. T h erefore, the following comments on the second version tend to addres s points of detail or cla r if ication rath er than fundamental issues.

Chapter 2. Source to tissue dose

Section 2.2, p. 2-3: “Because the saturation vapor pressure of H 2 SO 4 is extrem ely low, it will be rem o ved rapid l y by transf er to the a queou s phase of aerosol pa rtic les and c l ou d drops”. This is true only if aqueous particle s or cloud drops (or fog droplets) are present. For exam ple, under dry conditions, g a seous sulfu r ic acid m a y be transferred to particles to form dry particulate ammonium s u lfate.

p. 2-20: The SO 2 and sulfate concentration m a ps show n in Figures 2-8 and 2-9 originate from the CASTNET data using som e spatial interpolation m e thodology. Note that EP A’s Clean Air Market Division (CAMD) has deve loped som e data fusion approach that

com b ines the CASTNET data with a CMAQ si mulation to produced concentration m a ps that are im proved com p ared to the simp le CASTNET interpo l ation m a ps (CAMD contact: Melissa Rury).

Annex B

CTMs are som e tim es referred to as chem is try-transport m odels (e.g., p. B-15, line 1),

som e ti m e s as chem ical-transport m o dels (e.g., T i tle of Section B-5). It m a y be preferable to use a single term throughout the docum e nt.

p. B-7, lines 12-13: The statem ent that trans portation related sources only have a m i nor contribution to SO 2 am bient levels suggests a strong east- coast bias. In California, where point sources have low SO 2 em issions com p ared to the eas tern U.S., ships can be a m a jor contributing source to S O 2 concentrations. As a m a tter of fact, it would be appropriate to highligh t the recen t State of California regula tion on sulfur co ntent au thorized for diesel f u el of ships that a r e within the p r oxim ity of the Calif ornian coast.

p. B-17, line 6: The W e a t her Research & Fo recast (W RF) m o del is now the preferred

m e teorological m odel; add it in the parentheses before RAMS.

42p. B-22, line 14: The discussion points out th at a plum e-in-grid treatm ent affects the sim u lation results for ozone concentrations. Th is ef f

ect is du e to the im proved tre a tment of the NO x em issions when using a subgrid-scale re presentation of m a jo r point sources. In reality, the plum e-in-grid treatm e n t redist ributes the ozone concen trations with little effect on the overall ozone budget (e.g., Ka ram c handani et al., Development and application of a state-of-the-s cience plum e-in-grid m odel, J. Geophys. Res

., 107 , 4403- 4415, 2002). Since the docum e nt foc u ses on SO x , it should be noted that a plum e-in-grid
trea tm ent of SO x (and NO x ) em issions has a significant effect on secondary sulfate (and nitr ate ) f o rmation that m a y lead to u p to 15% less sulfate (or nitrate) formation from those m a jor point sources treated with a subgr id scale representation within the 3-D gridbased m odel (Karam chandani et al., Plum e- in-grid m odeling for particulate m a tter, Atmos. Environ

., 40 , 7280-7297, 2006).

p. B-25: It is true that comp ensation of errors may l ead to good m odel perform a nce for the wrong reasons and that the perform a nce evaluation of individual m odel com ponents is desirab l e. Therefore, it w ould be appropriate at this point to m e ntion the ef f

o rt m a de to evaluate the aqueous chem istry comp onent of SO x m odels either in the laboratory (W altrop et al., J. Atmos

. Chem

., 12 , 1-17, 1991) or in the at m o sphere (Daum et al., Atmos. Environ

., 18 , 2671-2684, 1984). Also, the evaluatio n of reactiv e plum e m o dels against aircraft data should be addressed.

p. B-25: This section only disc usses regional and global CT M for SO x and does not present any infor m ation on plum e dispersion m ode ls that are used to estim a te local (e.g., within 50 km ) i mpacts of m a jor SO x em ission sources. Since a plum e dispersion model (AERMOD) will be us ed to conduct the Risk a nd Exposure Assessm ent, it is desirab l e to have a section in the Annex that presents th is typ e of m odels, their lim itations and available perform a nce evaluation results.

43Dr. Frank E. Spei z er

Comm ents on SOx ISA – 2 nd Draft

Chapter 1 : Page 1.6, Figure 1-1. I do not find this partic ular figure that useful. Perhaps Gee & Payne-Sturg es, 2004 hav e sufficient text that acco mpanies the figure to m a ke it useful, but simp ly putting it out without adequate descriptors do not help. I could im agine many of the arrow s going in both directions if not in opposite directions . My suggestion would be either to expand the text of abandon the figure.

Page 1-6, section 1.3.3 the first sentence I this section needs to be m odifie d. There is another alternative way of sta ting wh at is b e ing s a id. Af ter all the r e ar e n o clin ical studies of to bacco sm oke and lung cancer . The studies are all epidem iological “association” studies. But the consistency and reproducibility and the magnitude of the association s are so overwhelm i ng that there are no alternativ e tenable explanations (there were early on but these have all but gone away).

Page 1-14, last box in table from previous pa ge. I think it wo uld be worth putting a lim it on “any level of exposure” Perhaps som e thing li ke reasonable level or at least in human non-toxicological levels.

Page 1-15 end of sectio n 1.3.8. Two issues that are not d i scussed here, (will need to be addressed som e where) but I though t should be part of this over all assessment of causality are “uncertainty” and “m argin of safety”. There are a v a rio u s inte rpretations of each and laying ou t s o m e def i nitions, even if they m i ght be dif f

e rent d e f i nition s us ed by dif f

e rent people, would be usef ul. W h at constitu tes a leve l of uncerta inty tha t is a c c eptab l e to a ll, 90% of regulators, 50% of regul ato r s etc? Sim ilarly, are there percen ts of uncertainly that are judged by advocacy groups that are diffe rent? W ith regard to m a rgin of safety ditto. Is it 20% m a rgin, 50%, 100%, 500%. A discussion up front in the docum ent might be a useful exercise and m i ght put CASAC, Staff, and adm i nistrative policy m a kers all

on sam e page.

Focus Question 1. I think the cataloging of the descriptions of how causation m i ght be determ ined is reasonable. The issue really isn’t ho w we generally understand how epidem iology, clin ical stud ies and an imal tox i colog y data a r e used. More important issues are the ones raised in m y last point above. I know th ere have been focus group discussions on the topic and there m a y even be som e published research on the subject. The m o re I think about it the more im portant is seem s to m e th at it be part of this chapter. Adding this

m a terial would substantially change the disc ussion and perhaps aid in what will be a difficult discussion is subseque nt chapters when causation gets interpreted in m a king

recomm endations for standards.

Additional Comm ents related to other Chapters.

44Figure 3-1, Page 3-12: This is an important figure that should be m o re thoroughly discussed. The figure indicates, from one of th e larger early studies that there are m a rked discrepancies in the responsiveness of indi vidual subjects. About 25% of the subjects

were essen t ially un respo n sive in term s of airway sensitivity below 2 ppm and another 25% were responsive below 0.5 ppm

. Thus, in assessing group data it is obviously the case that within any group the responders a nd the non-responders need to be considered separately if at all possible. In this study of asthm a tics, in which the presum ption would be that the response pattern would be random across the group, this clearly was not the case. I am s u re that I and others argued in the p a st th at th is raise s conce r n tha t in
attemp ting to justify a short term standard the f a ct tha t whic h 25% of the asthm a tic population would be affected cannot be de term ined prior to exposure argues for consideration in the setting of a standard w ith an adequate m a rgin of safety. I would contend that 25% of the population of asthm a tics is a larger fraction of the m o st sensitive population than one should be com f ortable to ignore in setting a s hort term standard. This argum ent did not win the day in 1994. The data since that tim e has further established the issue that th ere are w h at m i ght be called “super sensitive” groups of people and the whole issue of both what propor tion of the population should be protected and what the m a rgin of safety should be will n eed to be rev i s ited. In this case m a rgin of saf e ty is no t a surroga te f o r uncertain ty of effect but a m easure of the size o f the population to be protected.

In reaching a conclusion on page 3-46 the ge ne ra l im pression is tha t the e v idenced is suggestiv e. However, not taken into acc ount in reaching these conclusion s is the evidence tha t not a ll sub j ects within a ny gi ven po pulation are equally sens itiv e to th e im pact of SO2. In m y m i nd this phenom ena tip s the balance that regul ation of short term exposure is necessary.

This point is m a de even more effectivel y in Section 4.1.1 on page 4.2-3 along with figure 4-1. Given that sRaw is m easured as doub ling and FEV1 change is m easured as 15% decrease the range of changes from 0.2ppm to 0.6 is quite substantial and is consistent with a sign if icant advers e ef f

ect that will need to be m odeled in the risk a s sessm ent. A better job needs to be done in indicating th at subgroups of subjects appear to be m o re sensitive and m a y be driving the overall assessments in any specific study. These subgroups appear to exceed 5% to 13% for sRaw and FEV respectively, at the lowest levels of exposure tested (0.2 ppm ). The l ack of a threshold at these (relatively) high levels of exposure as compared to “bac kground of less than 15ppb m a kes straightforward extrapo l atio n uncertain. I am sure there are pe op le who are s e nsitive a t th ese lower le vels but finding an appropriate level and popul ation at risk will be difficult.

W ith regard to long term exposure and m o rt ality the larger (and better) conducted US studies are consistent but when assessed in the co ntext of all s t udies that m i ght be interpreted as negative leave the im pr ession th at the results are incons istent and therefore no prudent declaration of causal association can be m a de. Thi s seem s slightly off base as there is adequate reasoning given as to w hy som e studies m i ght be positive and som e negative and one simp ly cannot sum the total of studies

.

45Summ ary and Conclusions Chapter

The conclusion about the “very few monitors” P a ge 5-2, line 16 s uggests that one strong

recomm endation in this chapter is th at an expanded network of m onitors are need ed. This m a y or m a y not be true depending upon th e distribution seen at existing m onitors in that with a 1 hour m ean of 13ppb and a 99 th percentile value of 120-700ppb little inform ation is supplied other than the conclusi on given that the m a x is not contributing to the m ean. Som e full distributions m i ght help lead to the conclusion as to how m u ch additional m onitoring is necessary outside potential known hotspots.

Having the key finding summari zed and reproducing the summ arizing tables from the appendices is useful.

46Dr. Lianne Sheppard

Comm ents on SOx 2nd Draft ISA

Overall ass e ssment : This docum ent is m u ch i m pr oved from the previous version. Generally it flows better and m o re closely a tta ins its goa l of presenting an integ r ated science assessm ent of SO2 a nd its effect on health.

Charge question 1 : The Chapter 1 fram e work is reasonab l e.

Charge question 2 : Chapter 2 is better.

• There is b e tter characterization of the sp atial distribution of S O 2 m onitors, but the discuss i on is still lacking in the s e nse that there is no stra tif ic ation of analyses by

m i cro vs. neighborhood scale m onitors. This is an important feature to take into account in the interpretation of epidem iological studies. W h at fraction of monitors in each area falls in th ese categories ? How m a ny areas with S O 2 monitors lack any neighborhood scale m onitors?

• Section 2.5 is a good add ition and a g ood effort was m a de in 2.5.4 to discu ss im portant features of exposure assessm e nt for epidem iological studies. T h e availability of neighborhood scale mon itors should be brought into this discussion, as well as the reactivity of SO2.

Charge question 3 : Chapter 3 is m u ch m o re readable and w e ll organized.

Charge question 4 : The revision to the concentra tion-response m odeling discussion is reasonable. Discussion of vul nerable and susceptible groups is reasonable, but could possibly still benefit from a cat alogue (e.g. in a table) of all potential vulner abilities and susceptibilities that warrant consideration. The public health impacts section appears to be incom p lete. W h ile the gradation of re sponses and the prevalence of respiratory disorders tables are usef ul, these are not linke d to provide any infere nce about degree of public health importance of SO 2 exposure in the population.

Charge question 5 : There is good integration in Chapter 5.

Specific com m ents : To be added.

47Dr. George Thurston

Comm ents on SOx 2nd Draft ISA

1. The framework for causal determination and judging the overall wei ght of evidence, is presented in Chapter 1. Is this the appropr iate approach? Is it appropriately applied in the case o f

S O x ? How could the framework or its application be refined?

RESPONSE: Yes, I feel the staff has done an excellent job of pr operly incorporating and explaining both the weigh of evidence crite ria and the causality inference fram e w ork.

2. The discussion of the at mospheric chemistry o f

SO x has been expanded to provide a better characterization of the sp atial heterogeneity of urban SO 2 concentrations and correlations of SO 2 with other pollutants. We also included new sections describing the regulatory network and s iting criteria with maps of SO 2 and other monitors. A brief section describing the available 5-minute SO 2 data was also included. In addition, the relationships between out door, indoor, and personal exposure to SO 2 were clarified with additional details on sources of exposure error. Have these revisions to Chapter 2 improved its assessm ent of the currently available scientific knowledge on atmospheric sciences and ex posure and its relevan ce to the evaluation of human health effects presented in later chapters?

RESPONSE: Yes, this is much improved, but I w ould lik e to see a better represen tatio n of the trends in short-term 

### SO 2 concentrations (i.e., 1-hr m a ximum ) . W h i l e there has clearly been improve m e nt in annual average 

### SO 2 concentrations, as would be expected given the advent of the acid rain control program

, these efforts have focused on lowering overall tons of 

### SO 2 e m issions, and not on lowering m a xim u m i m pacts. So the question

rem a ins, have we seen a reduction in peak 

### SO 2 exposures near m a jor sources? As such, I would ask that plots of the distribution of 1-hour m a xi m u m values (for w h ich m a ny more sites are availab l e than f o r 5-m i nute peak s) ove r tim e to bette r eluc idate h o w m u ch im prove m e nt we are m a king in lowering peak 

### SO 2 exposures. Another issue I have with Chapter 2 is the inadequate coverage of the PM- 

### SO 2 interaction, and the potential for the co-presence of PM to increase lung dosage and health effects of 

### SO 2 over and above that indicated by controlled anim al and hum an populations using pure 

### SO 2 gas, without associated PM (w hich would be the case in the real world). W h ile the docum e nt include s research by Am dur on page 2-60, it does not include her work very clearly showing th e way that co-presence of PM along with 

### SO 2 increases th e im pact of acute 

### SO 2 exposure. While these studies are discussed in Chapter 3, they are p r ob able even m o re im porta nt to m e ntion here as well, as they are im portant to our understanding of 

### SO 2 doses in the real world. Now, while SO 2 has a relatively low Henry’s law constant, and it m i ght therefore b e expected th at little will be stored as sulfite in the aqueous phase in a naturally occurring aerosol, but the Am dur studies conversely imply that this 

### SO 2 -PM interac tion is a st rong one, so the docum ent

48needs to m o re thoroughly investigate this m ech anism

, and better sort out its possible role in enhancing the effects of a m bient 

### SO 2 . This might very well be an im portant consideration in trying to extrapolate from c ontrolled studies to effects in populations, as, if ignored, it m a y well mean that the hum a n health effects of elevated 

### SO 2 exposures will be underestim ated, and the 

### SO 2 concentrations required for a response would be underestim ated, as well. This consideration al so points to the greater relevance of using epidem iology for risk assessm ent, rather than controlled exposures to subjects, since epidem iology will have already inco rporated such PM- 

### SO 2 interactions that happen in the real world, but not in controlled exposure environm ents lacking PM.

3. In the revision, we reduced redundan cy, added summary sections and reorganized Chapter 3. In addition, d i scuss i ons o n poten tial confounding by and inter a ctions with copollu tants have been a dded. The 2nd draft ISA also includes addition a l analyses o f individual-level data from human clinical studies (S ections 3.1.3. and 4.1.1) that builds upon the analysis included in th e 1994 Supplement to the Second A ddendum. The toxico lo gy sections were reorganized to focus on st udies using more relevant concentrations of SO 2 and sections were added to better discuss mode of action and potential particle-SO 2 interactions. We are requesting CASA C review specifically on these ana lys e s as well as on the in teg r ati on of the overall evidence from the human clinical, animal to xicological, and epid emiological studies.

RESPONSE: W h ile this section m a kes advanc es, Section 3.1.5.2.5 is wholly inadequate. It igno res th e m a jor implication of th ese in te ractions: that exposure studies that do not include the potentiating effects of PM on 

### SO 2 exposures will ve ry likely have both underestim ated the size of 

### SO 2 effects and th e ov erestim a ted the 

### SO 2 lev e ls a t which such effects m a y be experienced in th e co-pre sence of particles (i.e . in the real world).

4. The section on concentration-response relationships in C hapter 4 was reorganized and revised to include analysis of individua l-level data from the human clinical studies and some additiona l dis c ussion of the diffic ulties of discernin g a threshold in population

- level da ta. In addition, r evis i ons wer e made to better characterize group s likely to b e s u sceptible o r vulnerab le to SO x and the potential size of the population at risk fo r SO x -related health effects. Finally, revisions were made to reduce redundancy with material presented in C hapter 3. Have the revisions made to Chapter 4 improved the characterization of the potential public health impact of SO x exposure?

RESPONSE: Again, in this chapter, there is little acknowledgem ent of the fact that m a ny of the clinical and anim a l studies were done using pure 

### SO 2 , without co-PM exposures, as would occur in the real world. T h is is especially critical in section 4.3.2, where the clin ical stud ies are used to indicate b e nchm arks of effects. Such a choice of levels at which various effects would occur must take in to accoun t the docum ented effects that PM would have on the size and threshold of effec t s by 

### SO 2 . For example, based on the work of Amdur and others, a conservative fa ctor to adjust for the copres en ce of PM

m i ght well be applied to estim ate the levels at which such clinical symp tom s might occur in the real w o rld.

495 . Revisions were made to be tter integrate findings from atmospheric sciences, ambient air data analyses, exposure assessm ent, dos imetry, and health evidence in Chapter 5. To what extent do these findings suppor t conclusions regarding causality of SO x relate d health effects at relevant exposures?

RESPONSE: The big issue that needs m o re discussion is why the epidem iology shows health effects association s at m u ch lower con centrations than do the clinical stud ies. T h e paragraph at the top of page 5-11 does disc uss one likely explanation of this apparent paradox: the effects of the fact that “aerosol particles act as carriers and deliver sulfurcontaining compounds more effec tively to the lower respirator y tract”. However, more discussion is needed here of the fact that th is m a y well accoun t f o r why epidem iologic a l associations are found at 

### SO 2 concentrations well below where effects are docum ented by clinical studies using pure 

### SO 2 exposures.

50Dr. James Ultman

Comm ents on SOx ISA – 2 nd Draft

General Co mments

This second draft of the ISA provides a signifi cant improve m e nt over th e first draft, both with respect to content a nd chapter organization.

Apparently, the f r am ing questions th at o r igin ally appeared on page 1-2 in the f i rs t dr af t of the ISA have been deleted from the second draft. The answers to several (but not all) of these qu estions can be culled from the fina l “Conclusions” section on page 5-12 of the revised docum ent. Given the importance of th ese questions in inform ing the REA as well as the final rulem a king, EPA staff s hould consid er reinserting the que stions into Chapter 1 and then e xplic itly ans w ering them in Chapter 5.

Comments on Chapter 2 and Char ge Question #1

General A m a jor im provem e nt in this ch apte r is the n e w mater i al on m onitor loca tions, particularly those 108 sites where 5-m i nut e averages have been recorded. I am , however, puzzled by the statem ent on lin es 1-2 of page 2-32 that: “Although these 5-m i nute data m eet AQS m i nim u m quality assu rance requirem ents...these data (are) very difficult to use precisely.” This appears to be the rationale for not including any actual data from these sites in the docum ent.

In fact, this very set of data, is used in the f i rs t dr af t REA to model the re lationship between peak and short-term a m bient SO2 c oncentrations. I suggest that disconnect between the ISA and REA be rem e died by incl uding som e data, in either a tabular or graphical form , regarding the peak and 1-hour short-term concentration data obtained from the m o nitors listed in tables 2-6 and 2-7. Is it possible, f o r exam ple, to exam ine and

com p are the relationsh i ps between the two c oncentration averages over tim e at various sites ?

The text indicates that ambient m oni tors are allowed to be sited at any vertical location between 2 and 15 m e ters above the ground (pg. 2-9 lines 3-4). Yet, there is vitually no discussion of vertical SO2 grad ients nor the errors such gr adients introduce when using

am bient concentration as a surrogate for ground-level conc entration. For exam ple, ground-lev e l concentrations near point source s will b e m u ch lower than concentration s recorded from m onitors high off the ground. It would be benefi cial for the ISA to provide a better qualitative and qua ntitative appreciation of this.

51Specific Comments

Page; lines

2-3; 10 &12 Define term inology (OH fo r hydr oxyl free radical and HO 2 for hydroperoxyl radical) im m e diately after the equation in which they first appear.

2-9; 3-4 Ho w large a d i fference between m onitored c oncen tra tions is a variation of 2-15 m difference in m onitor height likely to in troduce? How does this difference depend on distan ce to the point sou r ce?

2-14; 1 Make sure th at SLAMS and NAMS acrony m s have been previously defined.

2-23; 9 I assum e that you m ean “the Pears on correlation coefficients (r) for concentratio n data f r om multiple m onitors taken as pair s in these CMSA’s...”

2-26; 9-11 104 sites +15 sites is greater than th e total of 108 sites m e ntioned in the previous s e n t ence.

2-41; 5 Given the importance of exercise in prom oting health ef f

ects in asthm a tics, it is important that this be included as a p e rsonal activ ity in this lis t.

2-41;17-21 Incomp lete, run-on, sentence.

2-58; 14 Fo r cla r if ica tio n, it would b e helpf u l to add a phase indicati ng that the Henry’s Law constant is inversely proportional to solubility.

One-w ay flow versus c y clic flow ---
2-59; 4-5 W h at the tex t ref e rs to as “tota l re spir atory trac t a b sorption ” is presum ably the retained dose of SO2 over a comp lete respiratory cycle.

2-59; 18-20 In these experim e nts, the upper airw ays were isolated from the lower respiratory tract, and absorption was m easur ed during one-way flow (as opposed to the bidirection flow that occurs during a comp lete res p iratory cycle). This was also th e cas e for other investigations that are cited later on pages 2-59 and 2-60.

2-63; 6-8 It is precisely because of d e sorpti on du ring exhalation that cy clic flow experim e nts report sm aller absorp tio n efficienci es than one-w ay flow experim e nts. This explanation should be work ed into the discussion.

52Dr. Ronald E. Wyz ga

Comm ents on SOx ISA – 2 nd Draft

Charge question 3 : In the revision, we reduced re dundancy, added summ ary sections and reorganized Chapter 3. In addition, discussions on potential confounding by and interactions with copollutant s have been added. The 2 nd draft ISA also included additional analyses of individual-level data from hum a n clinical studies (Sections 3.1.3 and 4.1.1) that builds upon the analysis incl uded in the 1994 Supplem ent to the Second Addendum

. The toxicology sect ions were reorganized to focus on studies using m o re relev a nt con centr ation s of SO 2 and sections were added to better discuss m ode of action and potential particle-S O2 interactions. W e are requesting CASA C review specific a lly on these an alyses as well as on the integr ation of the overall evidence from the hum a n clin ical, anim al toxicolo gical and epidem iological studies.

Response to charge question : By and large I applaud th e efforts undertaken in the revision. It increases the presentation and di scussion of the hum an clinical studies, which I believe are extrem ely infor m ative about the h ealth effects of SO2. The focus is clearly upon respiratory responses, especially am ong as thm a tics. I previously had sent the Agency staff several papers of hum a n clinical studies, which have hopefully aided in this effort. They provide comp rehensive input to aid our understanding of responses of asthm a tics exposed to S O 2 in the cham ber. To s o m e extent the results presented in the ISA could have been extended to indicate the importance of other factors, such as the influence of routine asthm a medi cation and weather upon response.

I believe th e docum ent was large l y successf ul in integ r ating results ac ro ss scien tif ic disciplines although I note that several high lighted toxicological studies do utilize exposures orders of m a gnitude higher th an those which occur in the am bient environm ent. (e.g., 0.8-6mg/ m 3 and 1-2ppm SO 2). Special note should be m a de of t h e fact that thes e concentrations are extrem el y high and not representative of those that occur in the real world. The copollu tant issu e in epidem iological studies is a difficult one to address largely because few studies addr ess this issue sy stem atically, making it dif f i cult to r e solve this issue definitively. I would urge the docum e nt to ask for m o re system atic investig ation of this issue within ind i v i dual s t udie s

.

Overall co mments : T h is docum ent is substantially improved over the previous draft; it considers th e inform ative hum an clinical st udies in m o re detail and correctly focuses upon respiratory health, especially asthm a issues . I believe that relatively sm all changes in the docu m ent are needed. I give my speci fic comments below, which generally ask for further clarification or g r eater artic ulation of the presented material.

Specific co mments : p. 2-23, ll. 9-20: perhaps som e discussion a bout the dependence of exposure to SO2 on whether an individual (monitor) is in the plum e from a point source is warranted.

53p. 3-11; ll. 7-18: Another reason for the sim ilarity in response between mild and moderate/se v ere as thm a tics is tha t th e latter we re not able to exercise as intensely as the

m ild asthm a tics. It should also be noted that studies (e.g., G ong et al., 1996; Gong et al/. 2001; Linn et al. 1988 ) h a ve shown that m e dicated asthm a tics were not sensitiv e to S O 2
exposure.

p. 3-15, ll. 11: insert “exercising, non-m e dicated” before asthm a tics.

P. 3-16, l. 3: Linn et al., 1983 reporte d a significantly increased response among asthm a tic su bjects utilizing a m outhpiece fo r exp o sure as opp osed to thos e with

unencum bered breathing. This reference can be cited here.

p. 3-35, l. 10: “statistically”

p. 3-43, ll. 10-19: System atic exam i n ations of the potential influence of co-pollutants on study results are rare. Studies often consid er a lim ited set of co -pollutant w ith no discussion about why other co-p ollutants are not c onsidered. It would be useful to indicate the need for m o re system atic review of this issue within a study.

p. 3-45, ll. 1-7: It should be noted that th e panel studies found responses at am bient levels only when asthmatics were exercising.

p. 3-46, l. 31: reference should be given.

p. 3-47, ll. 14-20: It should be noted that exposure was by m o uthpiece. See comments for p. 3-16.

p. 3-49, ll. 16 and following: It should be not ed that the exposure levels in the studies cited in this section were extraordinarily high. T h is co mm ent applies to section 3.15.2.5.

p. 3.55, ll. 21-22: It should be noted that controlled hum a n studies did not find responses in adult atopi cs. (Linn et al., 1987).

p. 4-2, l. 1: Measurem ent error can also se rve to linearize dose -response estim ates.

p. 4.4, ll. 10-11. See comment for page 4-2.

p. 4-11, ll. 4-13: It m i ght also be notewor thy to indicate that asthm a tics on routine

m e dication do not appear to respond to SO2 while exercising.

54